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<meta name="description" content="Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely u …"><meta name="keywords" content="pmid:22232210, PMC3266790, doi:10.1172/JCI59526, Research Support, Non-U.S. Gov&#x27;t, Evita van de Steeg, Viktor Stránecký, Alfred H Schinkel, Animals, Bilirubin / analogs &amp; derivatives*, Bilirubin / metabolism, DNA Mutational Analysis, Female, Humans, Hyperbilirubinemia, Hereditary / blood, Hyperbilirubinemia, Hereditary / genetics, Hyperbilirubinemia, Hereditary / physiopathology*, Liver / metabolism*, Liver-Specific Organic Anion Transporter 1, Male, Mice, Mice, Knockout, Organic Anion Transporters / deficiency*, Organic Anion Transporters / genetics, Organic Anion Transporters, Sodium-Independent / deficiency*, Organic Anion Transporters, Sodium-Independent / genetics, Pedigree, Solute Carrier Organic Anion Transporter Family Member 1B3, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/22232210/"><meta property="og:description" content="Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely u …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/22232210/"><meta name="twitter:description" content="Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely u …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="wwDzO9MRsnPTTM24n7rQqFLyaRD5Rag4NjnErZfd2YCnNd8U0q4SUNhcIVlhKLOo">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="wwDzO9MRsnPTTM24n7rQqFLyaRD5Rag4NjnErZfd2YCnNd8U0q4SUNhcIVlhKLOo">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="wwDzO9MRsnPTTM24n7rQqFLyaRD5Rag4NjnErZfd2YCnNd8U0q4SUNhcIVlhKLOo">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="wwDzO9MRsnPTTM24n7rQqFLyaRD5Rag4NjnErZfd2YCnNd8U0q4SUNhcIVlhKLOo">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="wwDzO9MRsnPTTM24n7rQqFLyaRD5Rag4NjnErZfd2YCnNd8U0q4SUNhcIVlhKLOo">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="22232210">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1172/JCI59526"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=6619&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=22232210&amp;db=pubmed&amp;nlmid=7802877"
title="See full text options at American Society for Clinical Investigation"
data-ga-category="full_text"
data-ga-action="American Society for Clinical Investigation"
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><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--dm5migu4zj3pb.cloudfront.net-images-pubmed-jci_full_text_link_out.jpg" alt="American Society for Clinical Investigation full text link"><span class="text">
American Society for Clinical Investigation
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/22232210/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=22232210&amp;db=pubmed&amp;nlmid=7802877"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="22232210"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/22232210/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/22232210/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="22232210" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F22232210%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="wwDzO9MRsnPTTM24n7rQqFLyaRD5Rag4NjnErZfd2YCnNd8U0q4SUNhcIVlhKLOo"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
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Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
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Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.
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itemprop="contentUrl"
aria-describedby="figure-caption-0"
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data-image-width="665"
data-image-height="201"
data-image-alt="Figure 1"
data-pmc-id="PMC3266790"
data-figure-id="F1">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-0"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/0235b02596bb/JCI59526.f1.gif"
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<p> Figure 1. Increased plasma bilirubin glucuronide in… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1. Increased plasma bilirubin glucuronide in <i> Slco1a/1b <sup> / </sup> </i> mice is in part dependent on… </p>
</strong>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. Increased plasma bilirubin glucuronide in <i>Slco1a/1b<sup>/</sup></i> mice is in part dependent on Abcc3.
</strong>
<div class="figure-caption-contents">(<b>A</b>) BMG, (<b>B</b>) BDG, and (<b>C</b>) UCB levels in plasma of male wild-type, <i>Abcc3<sup>/</sup></i>, <i>Abcc2<sup>/</sup></i>, <i>Abcc2<sup>/</sup>Abcc3<sup>/</sup></i>, <i>Slco1a/1b<sup>/</sup></i>, <i>Slco1a/1b;Abcc3<sup>/</sup></i>, <i>Slco1a/1b;Abcc2<sup>/</sup></i>, and <i>Slco1a/1b;Abcc2;Abcc3<sup>/</sup></i> mice (<i>n</i> = 47). +Oatp1a/1b denotes strains possessing Oatp1a/1b proteins, and Oatp1a/1b denotes strains lacking Oatp1a/1b proteins. Data are mean ± SD. *<i>P</i> &lt; 0.05, ***<i>P</i> &lt; 0.001 compared with wild-type mice. Bracketed comparisons: <sup></sup><i>P</i> &lt; 0.05, <sup>††</sup><i>P</i> &lt; 0.01, <sup>†††</sup><i>P</i> &lt; 0.001. ND, not detectable; detection limit was 0.1 μM.</div>
</figcaption>
</figure>
<figure class="figure-item "
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itemprop="contentUrl"
aria-describedby="figure-caption-1"
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data-image-width="665"
data-image-height="199"
data-image-alt="Figure 2"
data-pmc-id="PMC3266790"
data-figure-id="F2">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/3d83f332f11f/JCI59526.f2.gif"
alt="Figure 2" />
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<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="665">
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<strong class="figure-label">
<p> Figure 2. In the presence of Oatp1a/1b,… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2. In the presence of Oatp1a/1b, but not in its absence, Abcc3 enhances biliary… </p>
</strong>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2. In the presence of Oatp1a/1b, but not in its absence, Abcc3 enhances biliary excretion of bilirubin glucuronides.
</strong>
<div class="figure-caption-contents">(<b>A</b>) BMG, (<b>B</b>) BDG, and (<b>C</b>) UCB output in bile of male wild-type, <i>Abcc3<sup>/</sup></i>, <i>Abcc2<sup>/</sup></i>, <i>Abcc2<sup>/</sup>Abcc3<sup>/</sup></i>, <i>Slco1a/1b<sup>/</sup></i>, <i>Slco1a/1b;Abcc3<sup>/</sup></i>, <i>Slco1a/1b;Abcc2<sup>/</sup></i>, and <i>Slco1a/1b;Abcc2;Abcc3<sup>/</sup></i> mice. Bile collected during the first 15 minutes after gall bladder cannulation was analyzed. +Oatp1a/1b denotes strains possessing Oatp1a/1b proteins, and Oatp1a/1b denotes strains lacking Oatp1a/1b proteins. Data are shown as mean ± SD (<i>n</i> = 47). **<i>P</i> &lt; 0.01, ***<i>P</i> &lt; 0.001 compared with wild-type mice. Bracketed comparisons: <sup></sup><i>P</i> &lt; 0.05, <sup>††</sup><i>P</i> &lt; 0.01.</div>
</figcaption>
</figure>
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itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
data-image-width="640"
data-image-height="172"
data-image-alt="Figure 3"
data-pmc-id="PMC3266790"
data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/cef6571b7cb9/JCI59526.f3.gif"
alt="Figure 3" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="640">
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<div class="caption-wrap">
<strong class="figure-label">
<p> Figure 3. Increased plasma bilirubin glucuronide in… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3. Increased plasma bilirubin glucuronide in <i> Slco1a/1b <sup> / </sup> </i> mice is reversed by human OATP1B1… </p>
</strong>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 3. Increased plasma bilirubin glucuronide in <i>Slco1a/1b<sup>/</sup></i> mice is reversed by human OATP1B1 and OATP1B3.
</strong>
<div class="figure-caption-contents">(<b>A</b>) BMG, (<b>B</b>) BDG, and (<b>C</b>) UCB levels in plasma of male wild-type and <i>Slco1a/1b<sup>/</sup></i> mice, and of the derived OATP1B1- and OATP1B3-transgenic strains (<i>Slco1a/1b<sup>/</sup>;1B1<sup>tg</sup></i> and <i>Slco1a/1b<sup>/</sup>1B3<sup>tg</sup></i>, respectively) (<i>n</i> = 58). Data are mean ± SD. **<i>P</i> &lt; 0.01, ***<i>P</i> &lt; 0.001 compared with wild-type mice. Bracketed comparisons: <sup>†††</sup><i>P</i> &lt; 0.001. Detection limit was 0.1 μM.</div>
</figcaption>
</figure>
<figure class="figure-item "
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<a class="figure-link"
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/7665b55d8c86/JCI59526.f4.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-3"
role="button"
data-image-width="584"
data-image-height="615"
data-image-alt="Figure 4"
data-pmc-id="PMC3266790"
data-figure-id="F4">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/80cdfc0a7fd1/JCI59526.f4.gif"
alt="Figure 4" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="584">
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<strong class="figure-label">
<p> Figure 4. RS families display deficiencies in… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4. RS families display deficiencies in <i> SLCO1B1 </i> and <i> SLCO1B3 </i> . </p>
</strong>
<div class="figure-caption-contents"><p> ( <b> A </b> ) Pedigrees of… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 4. RS families display deficiencies in <i>SLCO1B1</i> and <i>SLCO1B3</i>.
</strong>
<div class="figure-caption-contents">(<b>A</b>) Pedigrees of the investigated families. Black symbols denote RS index subjects. Parents in family CE4 had a documented common ancestor. Families CE1CE3 (only single individuals analyzed) are not shown. (<b>B</b>) Homozygosity regions in 8 RS index subjects and overview of detected mutations and polymorphisms. The genome map shows number and location of overlapping homozygosity regions in RS index subjects, gene content of the top candidate region on chromosome 12, and the genotypes forming all 3 identified RS haplotypes. Mutations crucial for RS are shown in red. chr, chromosome. (<b>C</b>) Sequences and electropherograms of the R1 and R2 deletion breakpoints. (<b>D</b>) Pathogenic point mutations in R1 and R3 haplotypes. Electropherograms indicate the c.1738C→T (p.R580X) mutation in <i>SLCO1B1</i> in probands CE1, CE2, and CE4 II.1 and the c.757C→T (p.R253X) and c.1747+1G→A mutations in <i>SLCO1B1</i> and <i>SLCO1B3</i>, respectively, in family P1.</div>
</figcaption>
</figure>
<figure class="figure-item "
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data-slide-index="4"
data-label-slug="figure-5">
<a class="figure-link"
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/6227e2fb1dab/JCI59526.f5.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-4"
role="button"
data-image-width="492"
data-image-height="354"
data-image-alt="Figure 5"
data-pmc-id="PMC3266790"
data-figure-id="F5">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64cc/3266790/214fd70f4b98/JCI59526.f5.gif"
alt="Figure 5" />
</a>
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<strong class="figure-label">
<p> Figure 5. Liver expression of OATP1B proteins… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5. Liver expression of OATP1B proteins in RS subjects and control. </p>
</strong>
<div class="figure-caption-contents"><p> With an anti-OATP1B1/3… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 5. Liver expression of OATP1B proteins in RS subjects and control.
</strong>
<div class="figure-caption-contents">With an anti-OATP1B1/3 antibody, basolateral membrane immunostaining of hepatocytes in centrilobular areas was intense in control. Asterisks indicate central veins, arrowheads bile canaliculi, and crosses sinusoids. OATP1B proteins were not detectable in RS subjects CE1 (haplotype R1), CE3 (haplotype R2), and P1 II.1 (haplotype R3). Scale bars: 25 μm (original magnification of CE1 and CE3, ×400; original magnification of P1 II.1 and control, ×200); inset: 5 μm (original magnification, ×1,000).</div>
</figcaption>
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<p> Figure 6. Hepatocyte hopping distributes the biliary… </p>
</strong>
</div>
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<strong class="figure-label">
<p> Figure 6. Hepatocyte hopping distributes the biliary excretion load of bilirubin glucuronides across the liver… </p>
</strong>
</div>
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 6. Hepatocyte hopping distributes the biliary excretion load of bilirubin glucuronides across the liver lobule.
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<div class="figure-caption-contents">(<b>A</b>) Schematic of liver lobule. Hepatocytes are organized around portal tracts, with branches of the portal vein (PV), hepatic artery (HA), and bile ducts (BD). The PV and HA deliver nutrient- and oxygen-rich blood, respectively, which flows through the sinusoids toward the central vein (CV). Basolateral (sinusoidal) membranes of hepatocytes are flushed with perisinusoidal plasma. Bile flows in the opposite direction toward bile ducts through canaliculi lined by canalicular membranes of hepatocytes. (<b>B</b>) Hepatocyte hopping cycle. UCB enters the hepatocytes via passive diffusion and/or transporters, which may include OATP1B1 and/or OATP1B3 in non-Rotor subjects. Conjugation with glucuronic acid by UGT1A1 to bilirubin glucuronides (BG) takes place in endoplasmic reticulum. BG is secreted into bile mainly by ABCC2. ABCG2 also can contribute to this process. Even under physiological conditions, a substantial fraction of the intracellular BG is rerouted by ABCC3 to the blood, from which it can be taken up by downstream hepatocytes via OATP1B1/3 transporters. This flexible off-loading of BG to downstream hepatocytes prevents saturation of biliary excretion capacity in upstream hepatocytes. Relative type sizes of UCB and BG represent local concentrations. Schematic modified, with permission, from ref. .</div>
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