UGT1A1 Genotyping – Drug-Induced Toxicity

UGT1A1 Genotyping – Drug-Induced Toxicity (e.g. Irinotecan, Nilotinib) and Gilbert’s Syndrome

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The molecular genetic analysis of the UGT1A1 gene enables the identification of clinically relevant polymorphisms, particularly the UGT1A1*28 and UGT1A1*6 variants, which play an important role in the diagnosis of Gilbert’s syndrome (Morbus Meulengracht) as well as in pharmacogenetics, especially regarding drug-induced toxicity (e.g. irinotecan, nilotinib).

Method:
Anticoagulant:
Recommendation:

Method:

Molecular genetics
Anticoagulant:

EDTA
Recommendation:

obligatory

UGT1A1 and Drug-Induced Toxicity
Pharmacogenetic diagnostics
Relevance for Drug Therapy
Gilbert’s Syndrome (Morbus Meulengracht)
Conclusion

UGT1A1 and Drug-Induced Toxicity

The UGT1A1 gene encodes the enzyme uridine diphosphate-glucuronosyltransferase 1A1, which plays a key role in phase II metabolism, particularly in the glucuronidation of bilirubin and various endogenous and xenobiotic substrates. Variants in this gene can result in reduced enzymatic activity and are associated with certain medical conditions as well as an increased risk of drug-induced side effects. Two particularly relevant allele variants are UGT1A1 *28 and UGT1A1 *6, which are of clinical significance especially in the context of Gilbert’s syndrome and the toxicity of irinotecan and nilotinib (Monaghan et al. 1996, Tukey et al. 2002, Nelson et al. 2021).

Pharmacogenetic diagnostics

To assess genetically reduced UGT1A1 enzyme activity, the two most common and clinically relevant variants of the UGT1A1 gene are tested, both of which have a clearly defined effect on enzyme function:

UGT1A1 *28 (A(TA)₇TAA promoter variant)
UGT1A1 *6 (c.211G>A, Gly71Arg)

Molecular genetic testing of UGT1A1 variants at MLL is based on fluorescence resonance energy transfer (FRET), with genotyping performed via melting curve analysis. The result differentiates whether the tested variant is heterozygous (present on one allele), homozygous (on both alleles), or not present (wild-type homozygosity with normal enzymatic activity). Other rare but functionally relevant variants outside the tested regions of the UGT1A1 gene cannot be excluded by this analysis.

Table 1: Overview of UGT1A1 Variants (modified from Nelson 2021)

Abbreviation	Variant Tested¹	RefSNP ID²	Enzyme Activity
UGT1A1*36	(TA)₅TAA	rs8175347	Increased
UGT1A1*1	(TA)₆TAA	rs8175347	Normal
UGT1A1*6	211G>A Gly71Arg	rs4148323	Decreased
UGT1A1*28	(TA)₇TAA	rs8175347	Decreased
UGT1A1*37	(TA)₈TAA	rs8175347	Decreased

¹ Based on UGT1A1-Transcript NM_000463.2
² From the Single Nucleotide Polymorphism (SNP) database

Individuals heterozygous for a decreased-function allele (e.g., UGT1A1 *1/*28) are considered intermediate metabolizers (IMs), while those carrying two such alleles (e.g., UGT1A1 *28/*28) are considered poor metabolizers (PMs) (Gammal et al. 2016).

Table 2: Expected UGT1A1 Phenotypes Based on Common Genotypes (modified from Nelson 2021)

Expected Phenotype	Common Genotypes [Rare Genotypes]
Normal Metabolizer (NM)	1/1 [1/36, 36/36]
Intermediate Metabolizer (IM)	1/28, 1/6 [1/37, 6/36, 28/36, 36/37]
Poor Metabolizer (PM)	6/6, 6/28, 28/28 [6/37, 28/37, 37/37]

UGT1A1 Variant Frequencies and Ethnic Differences

The prevalence of UGT1A1 *28 and *6 varies significantly across populations, influencing the distribution of homozygous and heterozygous carriers:

Table 3: Frequencies of UGT1A1 Alleles in Various Ethnic Groups (modified from Nelson 2021)

UGT1A1 Allele	African American/ Caribbean	Central/South Asian	East Asian	European	Latino	Sub-Saharan Africa
*1	3%	54%	71%	36%	21%	49%
*6	<1%	4%	15%	<1%	1%	0%
*28	37%	41%	15%	32%	40%	40%
*36	8%	0%	0%	0%	0%	7%
*37	6%	0%	0%	<1%	0%	4%

In European and Asian populations, the UGT1A1 *28 allele frequency is about 30–40%. In Europe, approximately 5–15% are homozygous (*28/*28) and 40–60% are heterozygous (*1/*28) (Hulshof et al. 2023).
In East Asians, UGT1A1 *6 is significantly more common (13–23%) than in Europe (<1%), with *6/*6 homozygotes found in about 5–10% of the population, and *1/*6 heterozygotes in 20–30% (Fukui et al. 2011).
Compound heterozygosity (*6/*28) also occurs and is particularly relevant in ethnically mixed populations.

These data are crucial for understanding interindividual differences in drug metabolism and bilirubin levels and must be considered in pharmacogenetic testing.

Pharmacogenetics: Relevance for Drug Therapy

UGT1A1 activity significantly affects the metabolism of various drugs, especially the chemotherapeutic agent irinotecan. Inhibition of UGT1A1 by nilotinib, a tyrosine kinase inhibitor, can also lead to adverse effects (Nelson et al. 2021).

Irinotecan

Irinotecan, a topoisomerase I inhibitor used in cancer therapy, is converted in the liver to its active metabolite SN-38, which is 100–1000 times more potent than the parent compound (Chabot 1997). SN-38 is lipophilic and requires phase II metabolism (glucuronidation) for inactivation. The resulting SN-38-glucuronide is water-soluble and excreted primarily via bile and around 30% via the kidneys (Slatter et al. 2000). Elevated plasma SN-38 levels are the primary cause of neutropenia; late-onset diarrhea is mainly due to excessive SN-38 accumulation in the intestines (Takasuna et al. 1996, Ratain & Innocenti 2010).

Clinical Relevance

Patients with UGT1A1 *28/*28, *6/*28, or *6/*6 genotypes are more likely to experience severe neutropenia, fever, and diarrhea during irinotecan therapy. Grade 3 or 4 side effects occur in 20–25% of cases. Approximately 7% of patients who develop severe neutropenia or fever after irinotecan treatment die from these complications (Douillard et al. 2000, Ratain 2002, Hoskins et al. 2007, Lankisch et al. 2008, Obradovic et al. 2008, Tam et al. 2009, Liu et al. 2014).

The FDA, Dutch Pharmacogenetics Working Group (DPWG), and French National Network of Pharmacogenetics (RNPGx) recommend a 25–30% dose reduction or alternative therapy in UGT1A1 *28/*28 homozygotes at therapy initiation. Later adjustments can be based on individual tolerability (Dailymed, Kennisbank, Quaranta & Thomas 2017).
According to RNPGx, UGT1A1 genotyping is advisable at standard doses (180–230 mg/m²) and essential for higher doses (>240 mg/m²) (Quaranta & Thomas 2017).
No dose adjustment is required for intermediate metabolizers (UGT1A1 *1/*28, *1/*6) (Kennisbank, Quaranta & Thomas 2017).
The German Federal Institute for Drugs and Medical Devices (BfArM) recommends considering lower starting doses of irinotecan for patients with reduced UGT1A1 activity, especially when doses exceed 180 mg/m² or in weakened patients (Rote-Hand-Brief, December 2021).

For detailed and updated dosing guidelines, see the relevant irinotecan pharmacogenetic therapy recommendations (Dean L., National Center for Biotechnology Information (US), 2018, Irinotecan Therapy and UGT1A1 Genotype).

Nilotinib

Nilotinib is a second-generation tyrosine kinase inhibitor used in patients with BCR::ABL1-positive chronic myeloid leukemia (CML). Unlike irinotecan, nilotinib is not metabolized by UGT1A1 but inhibits it, reducing bilirubin excretion (Fujita et al. 2011). This effect can be more pronounced in patients already genetically predisposed to low enzyme activity (Singer et al. 2007, Shibata et al. 2014).

Clinical Relevance:

Studies have shown that patients with UGT1A1 *6/*6, *6/*28, and *28/*28 genotypes have a higher risk of developing significant hyperbilirubinemia and other severe side effects (Singer et al. 2007, Abumiya et al. 2014, Shibata et al. 2014). However, not all studies confirmed a link between UGT1A1 genotype and hepatotoxicity (Iurlo et al. 2019).
Currently, there is insufficient clinical evidence to recommend preemptive nilotinib dose reduction based on UGT1A1 status. Still, genotyping could help identify patients at higher risk of toxicity who may require closer monitoring. For those developing hepatotoxicity, dosage adjustment guidelines are provided in the product information.

Gilbert’s Syndrome (Morbus Meulengracht)

Gilbert’s syndrome is a benign autosomal recessive metabolic disorder characterized by mildly elevated unconjugated bilirubin levels in the absence of liver or hemolytic disease. Symptoms may be non-specific (e.g., headaches, fatigue, abdominal discomfort) or entirely absent.

Pathogenesis

Gilbert’s syndrome results from impaired bilirubin conjugation with glucuronic acid in the liver due to UGT1A1 dysfunction. In most Caucasians, the condition is associated with the UGT1A1 *28/*28 genotype, which reduces bilirubin glucuronidation by 70% (Bosma et al. 1995). Interestingly, while bilirubin levels are generally higher in Asians, the *28 variant is rarer. Instead, other heterozygous coding region variants explain reduced UGT1A1 expression (Wagner et al. 2018).

Despite the mild hyperbilirubinemia, the benefits of slightly elevated serum bilirubin may outweigh the drawbacks. A protective effect against atherosclerosis is well documented (Vítek 2017), with broader positive impacts on metabolic, oncologic, inflammatory, autoimmune, and neurodegenerative diseases (Vítek 2019, Vitek et al. 2023). Patients with Gilbert’s syndrome also tend to gain less body fat with age and show improved insulin sensitivity and a lower risk of metabolic syndrome and type 2 diabetes. Bilirubin also appears protective against vascular diabetic complications (DiNicolantonio et al. 2018, Bianco et al. 2022). This may contribute to lower overall mortality and increased life expectancy in affected individuals (Chmielewski et al. 2017, Vitek et al. 2019).

It is important to note that the UGT1A1 *28/*28 genotype has incomplete penetrance: not all homozygous individuals develop clinical symptoms. Expression variability is likely influenced by gene-gene interactions and post-translational modifications of the UGT1A1 promoter (Vítek & Tiribelli 2021). Thus, Gilbert’s syndrome is defined phenotypically, with the *28/*28 genotype being only a predisposing factor.

Conclusion

UGT1A1 is a key gene in bilirubin and drug metabolism. The UGT1A1 *6 and *28 variants are clinically relevant, especially for Gilbert’s syndrome and treatment with irinotecan or nilotinib. Pharmacogenetic testing can help prevent toxicities and improve treatment safety. Ethnic differences in allele frequencies must be considered in diagnosis and therapy planning. Personalized medicine greatly benefits from integrating genetic information such as UGT1A1 status.

Status: July 2025

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