View source for Enzyme:UGT1A1

'''UGT1A1''' (UDP-glucuronosyltransferase 1A1) is a hepatic and intestinal phase-II conjugating enzyme whose clinical importance considerably exceeds the modest place it has historically held in pharmacology curricula. It is encoded by the ''UGT1A1'' gene at the ''UGT1A'' locus on chromosome 2q37.1, a complex locus in which a single shared 3' exon set is spliced to one of nine alternative first exons to produce the nine UGT1A isoforms; UGT1A1 uses the most upstream of those first exons. Among the family of glucuronidating enzymes, UGT1A1 is distinguished by a single non-redundant clinical role: it is the only meaningful enzymatic route by which the human body conjugates and clears bilirubin. The medicines it metabolizes are fewer in number than for the major cytochromes P450, but two of them, the cytotoxic [[Irinotecan|irinotecan]] and the HIV protease inhibitor [[Atazanavir|atazanavir]], sit at the centre of routine clinical pharmacogenomic practice and carry FDA labeling that explicitly references UGT1A1 genotype.

The history-of-medicine arc that produced this understanding spans almost exactly a century. In 1901, the French internist Augustin Nicolas Gilbert and his colleague Pierre Lereboullet, working at the Hôpital Saint-Antoine in Paris, published the first systematic description of a benign familial unconjugated hyperbilirubinemia they called ''la cholémie simple familiale'', the condition now universally known as Gilbert syndrome. The mechanism remained obscure through the rest of the twentieth century. Ninety-four years later, in 1995, Piter Bosma and colleagues at the Academic Medical Center in Amsterdam showed in the ''New England Journal of Medicine'' that Gilbert syndrome was caused by a TA-dinucleotide-repeat polymorphism in the ''UGT1A1'' promoter: the typical wild-type allele carries six TA repeats (TA6, designated ''UGT1A1\*1''), while Gilbert syndrome is associated with seven TA repeats (TA7, designated ''UGT1A1\*28''). The longer promoter reduces transcription by roughly 30%, producing the mild unconjugated hyperbilirubinemia of the syndrome.<ref name="bosma1995">Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury NR. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. ''New England Journal of Medicine''. 1995 Nov 2;333(18):1171-1175. PMID: 7565971.</ref> The clinical-pharmacology consequence followed quickly: the same variant that produces benign hyperbilirubinemia also reduces glucuronidation of any drug that depends on UGT1A1, and the cytotoxic [[Irinotecan|irinotecan]] became the canonical example.

== Tissue distribution ==
UGT1A1 is expressed at substantial levels in the liver (where the bulk of bilirubin conjugation occurs) and in the small-intestinal mucosa (where it contributes to first-pass conjugation of orally administered substrates). Extrahepatic and extraintestinal expression is detectable but pharmacologically minor for most substrates. The intestinal contribution matters specifically for orally administered substrates whose AUC depends on first-pass UGT1A1, and for the entero-hepatic recirculation of conjugates that are deconjugated by gut bacterial β-glucuronidases and reabsorbed (the mechanism behind the late-onset diarrhea that limits irinotecan dosing).

== Function and substrate spectrum ==
UGT1A1 catalyzes the conjugation of UDP-glucuronic acid to the hydroxyl, carboxyl, or amino group of a lipophilic substrate, producing a more water-soluble glucuronide conjugate that is excreted in bile or urine. The reaction is the canonical phase-II conjugation reaction; UGT1A1's substrate spectrum overlaps partly with the other UGT1A and UGT2B isoforms, but for two substrates it is essentially the sole pathway: '''bilirubin''' (the endogenous substrate that defines the enzyme clinically) and '''SN-38''' (the active metabolite of irinotecan).<ref name="tukey2000">Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. ''Annual Review of Pharmacology and Toxicology''. 2000;40:581-616. PMID: 10836148.</ref>

The table below collects the clinically important UGT1A1 substrates with each entry tagged by the contribution UGT1A1 makes to overall clearance (or, for the endogenous bilirubin entry, to physiological bilirubin disposal): '''major''' (UGT1A1 is the predominant route), '''moderate''' (UGT1A1 contributes meaningfully but other routes carry comparable load), '''minor''' (UGT1A1 contributes but other pathways dominate), and '''partial''' (one of several substantial routes). The list is curated for clinical relevance and is not exhaustive; see [[#Comprehensive substrate and interaction tables|Comprehensive substrate and interaction tables]] below for the authoritative maintained resources.

{| class="wikitable sortable mw-collapsible mw-collapsed" style="width:100%;"
|+ style="white-space:nowrap; text-align:left;" | near-complete UGT1A1 substrate table (click to expand)
! scope="col" | Substrate !! scope="col" | Therapeutic class !! scope="col" | UGT1A1 contribution !! scope="col" | Clinical notes
|-
| [[Acetaminophen]] || Analgesic / antipyretic (paracetamol) || minor || Predominantly cleared by UGT1A6, UGT1A9, UGT2B7, UGT2B15, and sulfation; UGT1A1 contribution is small.
|-
| [[Belinostat]] || HDAC inhibitor (peripheral T-cell lymphoma) || major || '''FDA labeling''': dose reduction in UGT1A1 PMs (\*28/\*28 homozygotes) because of accumulation toxicity.
|-
| '''[[Bilirubin]]''' || Endogenous heme-catabolism product || major || '''Canonical UGT1A1 substrate and the only meaningful enzymatic route by which the body clears bilirubin.''' UGT1A1 deficiency produces the Gilbert / Crigler-Najjar phenotype spectrum. The most pharmacologically consequential endogenous substrate of any human glucuronidating enzyme.
|-
| [[Buprenorphine]] || Opioid partial agonist || partial || Glucuronidation step (to buprenorphine-3-glucuronide); mixed UGT1A1, UGT1A3, UGT2B7.
|-
| [[Cabozantinib]] || Tyrosine kinase inhibitor (oncology) || moderate || UGT1A1 contributes to glucuronidation; FDA labeling does not currently require genotype-based dose adjustment.
|-
| [[Dolutegravir]] || HIV integrase inhibitor || major || UGT1A1 is the major glucuronidation route; CYP3A4 contributes. PMs have higher exposures but routine dose adjustment is not currently recommended.
|-
| [[Estradiol]] || Endogenous estrogen / hormone therapy || partial || Mixed UGT1A1 + UGT1A3 + UGT1A8 + UGT2B7; UGT1A1 contributes to the 3-glucuronide.
|-
| [[Estriol]] || Endogenous estrogen || partial || Same multi-UGT pattern as estradiol.
|-
| [[Ethinyl estradiol]] || Synthetic estrogen (oral contraceptive component) || partial || Mixed UGT1A1 + UGT1A3 + sulfation.
|-
| [[Etoposide]] || Topoisomerase II inhibitor (oncology) || minor || Mixed UGT1A1 + non-UGT routes.
|-
| '''[[Irinotecan]]''' || Topoisomerase I inhibitor (oncology); prodrug of SN-38 || major (via SN-38) || '''Canonical UGT1A1 clinical-pharmacogenomic substrate; FDA boxed warning territory.''' Irinotecan itself is hydrolyzed by carboxylesterases to SN-38, the active metabolite. SN-38 is then glucuronidated by UGT1A1 to inactive SN-38G. PMs (\*28/\*28) clear SN-38 substantially more slowly and have markedly elevated rates of grade 3-4 neutropenia and diarrhea. DPWG and FDA labeling both recommend dose reduction in PMs.
|-
| [[Lapatinib]] || Tyrosine kinase inhibitor (HER2; breast cancer) || moderate || UGT1A1 contributes; also a UGT1A1 inhibitor at therapeutic exposures.
|-
| [[Letrozole]] || Aromatase inhibitor (breast cancer) || moderate || Mixed UGT1A1 + non-UGT routes.
|-
| [[Lonafarnib]] || Farnesyltransferase inhibitor (progeria) || moderate || UGT1A1 contributes.
|-
| [[Nilotinib]] || Tyrosine kinase inhibitor (CML) || major || '''FDA labeling''' notes elevated risk of hyperbilirubinemia and dose-limiting elevations of total bilirubin in UGT1A1 \*28 homozygotes; nilotinib is also itself a UGT1A1 inhibitor (substrate AND inhibitor pattern).
|-
| [[Pazopanib]] || Tyrosine kinase inhibitor (RCC, sarcoma) || major || '''FDA labeling''': hepatotoxicity warning is partly UGT1A1-mediated; \*28 homozygotes have substantially elevated risk of hyperbilirubinemia.
|-
| [[Raltegravir]] || HIV integrase inhibitor || major || UGT1A1 is the predominant route; \*28 homozygotes have modestly elevated exposures.
|-
| [[Regorafenib]] || Tyrosine kinase inhibitor (colorectal, HCC) || moderate || UGT1A1 contributes; also a UGT1A1 inhibitor (which produces the hyperbilirubinemia seen on regorafenib therapy).
|-
| [[Sacituzumab govitecan]] || ADC delivering SN-38 (oncology) || major (via SN-38) || Same SN-38-glucuronidation pharmacology as irinotecan; FDA labeling cautions about elevated neutropenia risk in UGT1A1 PMs.
|-
| [[SN-38]] || Active metabolite of irinotecan; topoisomerase I inhibitor || major || See Irinotecan row; SN-38 is the actual UGT1A1 substrate that drives the clinical pharmacogenomic story of irinotecan.
|-
| [[Trifluridine-tipiracil]] || Antimetabolite combination (colorectal) || moderate || Tipiracil component partly UGT1A1-cleared.
|}

== Phenotype categories ==
UGT1A1 phenotype-to-genotype mapping is somewhat simpler than for CYP2D6 because the \*28 allele is by far the dominant clinically relevant variant in most populations, and the gain-of-function story is essentially absent.

* '''Normal metabolizer (NM)''': two wild-type \*1/\*1 (TA6/TA6) diplotype. Roughly 40 to 50% of European-ancestry populations.
* '''Intermediate metabolizer (IM)''': one wild-type and one reduced-function allele (\*1/\*28, \*1/\*6, \*1/\*37 typical). Roughly 35 to 45% of European-ancestry populations.
* '''Poor metabolizer (PM)''': two reduced-function alleles (\*28/\*28, \*6/\*6, \*37/\*37, or mixed). The biochemical phenotype of Gilbert syndrome; in clinical practice, roughly 10% of European-ancestry, 5 to 10% of African-ancestry, and 1 to 5% of East Asian populations.

There is no '''ultra-rapid metabolizer''' category in current UGT1A1 phenotype conventions; gain-of-function alleles are not established for this enzyme in the way that ''CYP2C19\*17'' is for CYP2C19.

A separate, more severe end of the phenotypic spectrum is occupied by '''Crigler-Najjar syndrome''', the homozygous-null state for UGT1A1. Type I Crigler-Najjar (essentially complete loss of UGT1A1 activity) produces severe neonatal unconjugated hyperbilirubinemia, kernicterus risk, and historically required lifelong phototherapy or liver transplant; type II Crigler-Najjar (partial loss) is intermediate in severity and often responds to phenobarbital-induced UGT1A1 upregulation. The Crigler-Najjar variants are private alleles spread across the ''UGT1A1'' coding sequence rather than the \*28 promoter polymorphism.

== Major variants ==
* '''\*1''', the reference wild-type promoter (TA6 / A(TA)6TAA). Fully functional. The most common allele in most populations.
* '''\*28''' (rs8175347, A(TA)7TAA, TA7 promoter), reduced-function, the classic Gilbert syndrome allele. Allele frequency roughly 30 to 40% in European-ancestry, 40 to 55% in African-ancestry, 10 to 20% in East Asian populations.
* '''\*6''' (rs4148323, G71R, Gly71Arg), reduced-function, the most clinically relevant variant in East Asian populations where it reaches allele frequencies of 13 to 23% (versus less than 1% in European-ancestry populations). Effect size on UGT1A1 activity is comparable to or larger than \*28.
* '''\*37''' (A(TA)8TAA, TA8 promoter), reduced-function with greater activity loss than \*28; allele frequency 3 to 7% in some African-ancestry populations, essentially absent in European-ancestry. Underrepresented in many testing panels, a known health-equity gap parallel to the CYP2C9 \*5/\*6/\*8/\*11 situation.
* '''\*36''' (A(TA)5TAA, TA5 promoter), modestly increased-function in some studies; allele frequency 3 to 7% in African-ancestry populations.
* '''Crigler-Najjar private variants''', coding-sequence missense and nonsense alleles producing complete or near-complete UGT1A1 inactivation. Catalogued in the Pharmacogene Variation Consortium (PharmVar) and clinical-genetic databases.

== Inhibitors ==
UGT1A1 inhibition by a co-prescribed medicine produces a phenocopy of UGT1A1 deficiency for the duration of the inhibitor's effect, with predictable consequences for bilirubin and for any UGT1A1 substrate. The most clinically important inhibitors:

* '''[[Atazanavir]]''', a competitive UGT1A1 inhibitor at therapeutic exposures. The hyperbilirubinemia produced on atazanavir therapy is a UGT1A1-inhibition phenocopy of Gilbert syndrome, and is amplified in \*28 carriers to the point of clinically apparent jaundice. CPIC publishes specific guidance for atazanavir prescribing in UGT1A1 PMs (consider an alternative protease inhibitor).<ref name="gammal2016">Gammal RS, Court MH, Haidar CE, Iwuchukwu OF, Gaur AH, Alvarellos M, Guillemette C, Lennox JL, Whirl-Carrillo M, Brummel SS, Klein TE, Caudle KE. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. ''Clinical Pharmacology and Therapeutics''. 2016 Apr;99(4):363-369. PMID: 26417955.</ref>
* '''[[Indinavir]]''', similar competitive inhibition; produces Gilbert-pattern hyperbilirubinemia, particularly in \*28 carriers.
* '''[[Sorafenib]]''', '''[[Regorafenib]]''', '''[[Nilotinib]]''', '''[[Pazopanib]]''', '''[[Erlotinib]]''', '''[[Gefitinib]]''': several tyrosine kinase inhibitors of the multi-kinase and EGFR classes are UGT1A1 inhibitors, and contribute to the hyperbilirubinemia commonly observed during TKI therapy in oncology. The interaction matters specifically when a UGT1A1-dependent cytotoxic (irinotecan) is co-administered with one of these TKIs.

== Inducers ==
UGT1A1 is inducible but more weakly than the major cytochromes P450. The clinically relevant inducer is '''phenobarbital''', which upregulates UGT1A1 by a constitutive androstane receptor (CAR)-mediated mechanism and has been used therapeutically since the 1960s to treat type II Crigler-Najjar syndrome (and, historically, severe neonatal jaundice). '''[[Rifampin|Rifampin]]''' induces UGT1A1 modestly via pregnane X receptor signaling and can reduce exposures of UGT1A1-cleared medicines. Auto-induction is less prominent than for CYP3A4.

== Clinical implications, summary ==
The clinical pharmacogenomics of UGT1A1 is organized around three distinct clinical questions:

'''Irinotecan dosing.''' The Dutch Pharmacogenetics Working Group (DPWG) issued a 2023 guideline recommending a starting-dose reduction of 30% for UGT1A1 \*28/\*28 homozygotes receiving irinotecan in standard chemotherapy regimens, with the option to titrate up to full dose if neutropenia does not occur.<ref name="hulshof2023">Hulshof EC, Deenen MJ, Nijenhuis M, Soree B, Soree TN, de Boer-Veger NJ, Buunk AM, Houwink EJF, Risselada A, Rongen GAPJM, van Schaik RHN, Touw DJ, Wilffert B, Swen JJ, Guchelaar HJ. Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan. ''European Journal of Human Genetics''. 2023 Sep;31(9):982-987. PMID: 36443464.</ref> The original mechanistic and clinical data underpinning this recommendation comes from the late-1990s work of Lalitha Iyer and colleagues at the University of Chicago, who first identified UGT1A1 as the SN-38 glucuronidating enzyme,<ref name="iyer1998">Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. ''Journal of Clinical Investigation''. 1998 Feb 15;101(4):847-854. PMID: 9466980.</ref> and from the 2004 Innocenti et al. study that prospectively established the \*28/\*28 genotype as a predictor of severe neutropenia.<ref name="innocenti2004">Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramírez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. ''Journal of Clinical Oncology''. 2004 Apr 15;22(8):1382-1388. PMID: 15007088.</ref> The FDA updated irinotecan labeling in 2005 to reflect this genotype-toxicity relationship; UGT1A1 genotyping is now a standard pre-treatment consideration in many oncology programs, although it has not become universal.

'''Atazanavir hyperbilirubinemia.''' UGT1A1 \*28 homozygotes treated with atazanavir reliably develop clinically apparent unconjugated hyperbilirubinemia and visible jaundice, which is typically benign biochemically but is cosmetically distressing and is a frequent driver of patient-initiated discontinuation. CPIC's 2016 guideline recommends considering an alternative protease inhibitor in \*28/\*28 patients in whom the cosmetic burden of jaundice would be unacceptable.<ref name="gammal2016" />

'''Crigler-Najjar and neonatal jaundice.''' Type I Crigler-Najjar (homozygous loss-of-function private variants) is a rare lethal-if-untreated paediatric condition managed with phototherapy and ultimately liver transplant; type II responds to phenobarbital-induced UGT1A1 upregulation. The genetic and biochemical understanding of UGT1A1 has been central to neonatal-jaundice management and the recognition that breastfeeding-associated and physiological neonatal jaundice both reflect, in part, the relative immaturity of UGT1A1 expression in the first weeks of life.

== Comprehensive substrate and interaction tables ==
The substrate and interaction tables on this page are curated for clinical relevance, not for completeness. Two authoritative external resources maintain comprehensive lists of UGT1A1 substrates, inhibitors, and inducers (the canonical Flockhart cytochrome P450 table does not cover the glucuronidating enzymes), and the wiki recommends them to any reader who needs an exhaustive look-up:

* '''U.S. Food and Drug Administration Drug Development and Drug Interactions Table''', the regulatory-grade list FDA uses for labeling and clinical-trial design decisions. Covers UGT1A1 substrates, inhibitors, and inducers alongside the cytochromes P450. Available via the FDA Center for Drug Evaluation and Research clinical drug interaction page.
* '''PharmGKB''', the pharmacogenomics knowledge base hosted at Stanford University; the UGT1A1 gene page indexes substrate-, inhibitor-, and inducer-relationships with their underlying primary literature, and links each gene-drug pair to the CPIC or DPWG dosing guideline where one exists.<ref name="pharmgkb2021">Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, Klein TE. An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. ''Clinical Pharmacology and Therapeutics''. 2021 Sep;110(3):563-572. PMID: 34216021.</ref> Available at https://www.pharmgkb.org/.

For a comprehensive review of UGT1A1 and the rest of the human UGT family covering regulation, expression, substrate spectrum, and disease, the Tukey and Strassburg 2000 review in ''Annual Review of Pharmacology and Toxicology'' remains the standard reference.<ref name="tukey2000" />

== See also ==
* [[Phenotype:UGT1A1 poor metabolizer]]
* [[Phenotype:UGT1A1 intermediate metabolizer]]
* [[Phenotype:UGT1A1 normal metabolizer]]
* [[Enzyme:CYP3A4]], [[Enzyme:CYP2D6]], [[Enzyme:CYP2C19]], [[Enzyme:CYP2C9]] (the major drug-metabolizing cytochromes P450 covered elsewhere in the wiki)
* [[Irinotecan]], [[Atazanavir]], [[Raltegravir]], [[Dolutegravir]] (canonical clinical UGT1A1 examples)
* [[Bilirubin]], [[Gilbert syndrome]], [[Crigler-Najjar syndrome]] (the endogenous-substrate clinical context)
* [[:Category:Drug-metabolizing enzymes]]

== References ==

<references/>

[[Category:Drug-metabolizing enzymes]]
[[Category:Pharmacogenomics]]