Many pharmaceuticals and other xenobiotics (such as drugs, environmental and industrial chemicals) and endobiotics (such as bilirubin, bile acids, fatty acids, 20-hydroxyeicosatetraenoic acid, thyroid hormones, and steroids) are non-polar, lipid-soluble substances. Their phase II metabolism (also known as conjugation reaction) yields polar and hydrophilic compounds by adding an endogenous polar group (e.g., glucuronic acid, sulphate, glutathione, or acetyl) to a lipophilic substrate. This enhances their clearance with urine and bile and works as a detoxification mechanism (1, 2, 3). In humans, the most common conjugation pathway is glucuronidation due to a wide range of potential substrates and high availability of glucuronic acid, an endogenous chemical derived from cofactor uridine diphosphate glucuronic acid (UDP glucuronic acid), which covalently binds to a nucleophilic substrate to form a water-soluble conjugate and uridine diphosphate. Glucuronidation is mediated by uridine diphosphate glucuronosyltransferases (UDP glucuronosyltransferases, UGTs), enzymes present in many tissues (mainly in the liver, gut, and kidneys) and localised in the endoplasmic reticulum, which implies lipophilic properties of their substrates (2, 3, 4). Furthermore, glucuronidation is essential for the clearance of drugs such as analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), antineoplastics, antiepileptics, and benzodiazepines (5).
Most glucuronides are less active than their parent substances, but there are exceptions, such as morphine-6-glucuronide, a strong μ-opioid receptor agonist, whose activity is even higher than that of morphine (6). According to their amino acid sequence, UGTs in humans generally belong to four families: UGT1, UGT2, UGT3, and UGT8. The most significant drug-conjugating UGTs are members of the UGT1A and UGT2B subfamilies. Their isoforms are extensively expressed in the intestine and the gut, where they play a crucial role in facilitating the first-pass metabolism of various pharmaceutical and biological phenolic substances. Some like UGT1A1, 1A2, 1A3, 1A6, 1A9, 2B7, and 2B15 are clinically the most important (4).
UGTs have different selectivity for specific substrates, but it occasionally overlaps, as several isoforms can often participate in glucuronidation of the same substrate. From a toxicological standpoint, this feature is beneficial, because if one isoform malfunctions, it does not always entail lower clearance and detoxification (7).
Considering that there are many drug substrates (Table 1) (3, 8), UGTs are involved in various drug-drug interactions of which the inhibitory ones are a key source of adverse reactions to drugs. A number of medicines inhibit UGTs in vitro, but not many are considered clinically relevant (3). Those that are, most often affect uridine diphosphate glucuronosyltransferase-2B7 (UGT2B7) (9). Immunosuppressants tacrolimus and cyclosporine are an example of highly effective UGT inhibitors (10). By engaging UGTs, valproic acid inhibits the metabolism of lamotrigine, lorazepam, and zidovudine, while probenecid inhibits the metabolism of acetaminophen, clofibrate, lorazepam, and zidovudine (3). Zidovudine pharmacokinetics is also significantly altered in HIV patients receiving fluconazole, which inhibits glucuronidation (3).
The UGT2B7 enzyme is encoded by UGT2B7, a 16 Kb, six-exon gene located on chromosome 4q13. This gene is highly polymorphic and has a number of non-synonymous, synonymous, intron and promoter single nucleotide polymorphisms (SNPs) (11). Structurally, the N‑terminal substrate-binding domain of the gene product UGT2B7 is encoded by the first and second exon, while the highly conserved C-terminal UDP‑glucuronic acid cofactor-binding domain is encoded by the area between the third and sixth exon. Furthermore, UGT2B7 genetic variations reveal ethnic diversity and have a wide range of inter-individual differences in glucuronidation activity (12). Reports on how UGT2B7 polymorphisms influence its enzyme activity are still contradictory. Some studies report higher and others lower activity, which suggests that the activity of UGT2B7 may be substrate- dependent (13, 14, 15, 16, 17, 18).
Genetic association studies indicate that the UGT2B7*2 polymorphism has an important role in moderating both pharmacokinetic and pharmacodynamic properties of substrate drugs due to lower enzyme activity and glucuronidation rate. In addition, this polymorphism moderates toxic and/or carcinogenic effects of other endogenous and exogenous substrate metabolites and may have a part in disease pathogenesis (19), including vasoconstriction, hypertension, atherosclerosis, and renal injury through lower glucuronidation of 20-hydroxyeicosatetraenoic acid (20-HETE) (20, 21).
Considering that UGT2B7 polymorphisms may up (22, 23, 24) or lower (25, 26) glucuronidation and excretion of a number of substrates, it is clinically important to predict metaboliser phenotypes of specific UGT2B7 polymorphisms and personalise treatment.
For this reason, several studies have investigated the distribution of different polymorphisms of this gene in different populations, but no such study has been carried out in Croatia, save for a very limited study on UGT2B7 c.-161C>T frequency in adult patients with epilepsy (27).
The aim of this study was to complement our earlier genotyping research of the UGT2B7 c.-161C>T (rs7668258) polymorphism (and consequently of the rs7439366 variant) in the Croatian population as this specific polymorphism is in strong linkage disequilibrium (LD) with UGT2B7*2 (rs7439366)variant (21, 28) and has a considerable impact on the pharmacokinetics of lamotrigine (29, 30, 31, 32). In view of the cases in clinical practice, we believe its genotypes may result in variable kinetics and predisposition to side effects of several substrate drugs (21, 32). Our secondary aim was to compare its genotype frequencies with other ethnicities in Europe and worldwide.
Participants and methods
Study population
The study included 501 Caucasian participants from different parts of Croatia, 252 men and 249 women (median age 34 years; range 2–77 years), who make a good sample of mixed Croatian population. All participants were recruited at the University Hospital Centre Zagreb to which they were referred for regular pharmacogenetic testing with different diagnoses and pharmacotherapy. The study includes pharmacogenetic data collected from 2016 to 2022.
For comparison, we relied on the Genome Aggregation Database (gnomAD) v.2.1.1 (33, 34) and 1000 Genomes database (35, 36) as sources of allele population frequencies worldwide.
Genotyping
For genotyping, 3 mL of blood samples were collected into BD Vacutainer™ K3EDTA tubes (Becton, Dickinson and Company, Franklin Lakes, NJ, USA). Genomic DNA was extracted from whole blood using the QIAamp® kit (Qiagen, Hilden, Germany). For genotyping we relied on the TaqMan® Drug Metabolism Genotyping Assay for UGT2B7 c.‑161C>T (rs7668258; assay ID: C__27827970_40) (Applied Biosystems, Carlsbad, CA, USA) and ran it on a 7500 Real-Time PCR System (Applied Biosystems, Carlsbad, CA, USA) according to the manufacturer’s instructions.
Data analysis
Allele and genotype frequencies were counted directly and data entered into Microsoft Excel 2016 (Microsoft Corporation, Redmond, WA, USA). Testing for Hardy-Weinberg equilibrium (HWE) was performed with online HWE calculator Gene Calc (37).
Results and discussion
The distribution of UGT2B7 c.-161C>T is consistent with HWE (p=0.92113). Our Croatian population had almost identical distribution of participants homozygous for the UGT2B7 c.-161C (23.95 %, 120 participants) and UGT2B7 c.-161T (25.15 %, 126 participants) allele. The number of participants heterozygous for the UGT2B7 c.-161CT was 255 (50.9 %). The frequency of the variant UGT2B7 c.-161C>T allele was 0.506, and in this respect the Croatian population does not differ from the bulk of Europe (Table 2) with the exception of the Finnish population. It turns out to be somewhat more common in Croatian than in African/African American, East and South Asian, Latino/Admixed American, and Ashkenazi Jewish populations (Table 3).
UGT2B7 c.-161C>T genotype frequencies in the Croatian population and data on European populations (35, 36)
Gene - allele
Genotype
Croatian populationa
European population
CEUb
FINb
GBRb
IBSb
TSIb
UGT(rs76682582B7 c.-161) C>T
C/C
0.240
0.250
0.232
0.333
0.220
0.271
0.196
C/T
0.509
0.529
0.576
0.434
0.505
0.551
0.570
T/T
0.251
0.221
0.192
0.232
0.275
0.178
0.234
a Frequencies determined in this study. b Allele frequencies from the 1000 Genomes database: CEU – Utah residents with Northern and Western European ancestry from the CEPH collection; FIN – Finnish in Finland; GBR – British in England; IBS – Iberian population; TSI – Tuscans in Italy
UGT2B7 c.-161C>T allele frequencies in the Croatian population and data on worldwide populations (33, 34, 35, 36)
NCBI dbSNP ID
Alleles
Croatian populationa
EURb
FINb
AFRb
EASb
SASc
AMRb
AJb
Otherb
UGT2B7 c.-161C>T rs7668258
C
0.4940
0.4624
0.5599
0.7078
0.7057
0.6010
0.6896
0.5625
0.5221
T
0.5060
0.5376
0.4401
0.2922
0.2943
0.3990
0.3104
0.4375
0.4779
a Frequencies determined in this study. b Data from the Genome Aggregation Database (gnomAD): EUR – non-Finnish Europeans; FIN – Finnish; AFR – African/African American; EAS – East Asian; AMR – Latino/Admixed American; AJ – Ashkenazi Jewish. c Data from the 1000 Genomes database: SAS – South Asia
Our results in 500 participants are in line with the Croatian study in adult epilepsy patients reporting of UGT2B7 c.-161C>T genotype frequencies of CC (24.9 %), CT (47.8 %), and TT (27.3 %), and overall variant T allele frequency of 51.2 % (27). They are also in line with reports for other European populations, with the exception of the Finnish (33, 34, 35, 36). Considering other races, the polymorphism at locus UGT2B7 c.-161C>T (rs7668258) notably varies from African/African Americans, East and South Asians, and Latino/ Admixed Americans.
Considering that this is not a genetic association study, our study is limited to genotyping only one rs7668258 variant and to determining the c.-161C>T frequency in the Croatian population. Future studies should examine the frequency of different haplotypes that include the UGT2B7 -c.161 C>T or c.802C>T (*2) variant and their role in glucuronidation variability of different substrates. Future research should also put more focus on the association between substrate metabolism and the UGT2B7 c.-161C>T polymorphism and its genotype distribution in different conditions associated with this variant (e.g. oxidative stress, hypertension, atherosclerosis, renal disease, cancer) (20, 21, 35, 38, 39, 40, 41). As the activity of UGT2B7 encoded by the c.-161C>T variant allele carriers is substrate-specific and confirmed for different drugs, further research should also focus on examining the clinical relevance of this polymorphism for other substrate drugs such as fenofibrates. The relevance of UGT2B7 variants may be particularly important in combined therapy with drugs having the same UGT2B7 metabolic pathway (e.g. diclofenac, morphine, fenofibrate). In patients receiving such therapy it would be important to understand drug-drug-gene interactions that influence drug effectiveness and side effects, especially in terms of different UGT2B7 genotype/phenotype groups.
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