Variation of hepatic glucuronidation: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4

Abstract

UDP-glucuronosyltransferases are a family of drug metabolizing enzymes contributing to hepatic drug metabolism and protection against environmental toxins. The aim of this study was to identify polymorphisms at the human UGT1A gene locus and to characterize their function and potential association with hepatocellular carcinoma (HCC). Genomic DNA from the blood of 363 subjects (128 patients with HCC, 235 blood donors) was analyzed for polymorphisms of the UGT1A3, UGT1A4, UGT1A8, UGT1A9, UGT1A10 genes using polymerase chain reaction, sequencing analysis. Recombinant variant UGT protein was analyzed by activity assays. In the UGT1A8 gene an A173G variant and a conserved G to A exchange at position 765 were detected in 25% and 15%. UGT1A9 exhibited two variants C3Y and M33T in 1% and 3%. UGT1A10 exhibited conserved nucleotide exchanges (128 G3 A and 696 C3 T) in 2% and 13%. In the UGT1A3 gene a W11R, a V47A variant, and a conserved G to A exchange at position 81 with an incidence of 65%, 58%, and 65%, respectively, were identified. UGT1A4 exhibited a P24T and an L48V variant in 8% and 9%. UGT1A SNPs were not associated with HCC. UGT1A4 P24T and L48V exhibited reduced glucuronidation activities: ␤-naphthylamine 30% and 50%, and dihydrotestosterone 50% and 0%, respectively. In conclusion, the high prevalence of SNPs throughout the human UGT1A gene locus illustrates a genetic basis of interindividual variations of hepatic metabolism. Two polymorphisms of the hepatic UGT1A4 protein show a differential metabolic activity toward mutagenic amines and endogenous steroids, altering hepatic metabolism and detoxification. (HEPATOLOGY 2004;39:970 -977.)

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

“…Several mutants were expressed in COS-7 cells, and it was determined that contrary to several UGT mutants with diminished activity, the UGT1A3 variants W11R and W11R þ V47A exhibited much greater activity toward estrone than the wild type. The same SNPs were concurrently reported by another group, where the authors additionally characterized the prevalence of these polymorphisms in 470 healthy controls and 258 hepatocellular carcinoma (HCC) patients (Ehmer et al, 2004). No significant difference was found in the allele frequencies between controls and cancer patients.…”

“…Table 2 summarizes some functionally relevant UGT1A3 polymorphisms. The allele frequencies reported in two independent studies are similar, despite the different populations characterized in each study (Ehmer et al, 2004;Iwai et al, 2004). Iwai et al (2004) reported six single-nucleotide polymorphisms (SNPs) in exon 1 of UGT1A3.…”

“…Of these 21 mutations, eight lead to aminoacid changes, five are silent mutations, whereas the remaining eight are in non-coding regions of the gene (Ehmer et al, 2004;Saeki et al, 2005a). Haplotype analysis of the detected SNPs resulted in the assignment of 16 observed haplotypes in a Japanese population (Saeki et al, 2005a).…”

Influence of Concomitant Antiepileptic Drugs on Plasma Lamotrigine Concentration in Adult Japanese Epilepsy Patients

“…Thus, this polymorphism causes an increase of glucuronidation activity. It has been reported that the frequency of UGT1A4 (142T>G) polymorphism is 8% in Caucasians 20) and 12% in Japanese, 21) no marked difference. On the other hand, the frequency of UGT2B7*2 (802C>T) polymorphism, which is linked with −161C>T, 22) was reported to be 48.9-53.7% 23,24) in Caucasians and only 24.4-29.3% 24,25) in Japanese.…”

The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

“…Significant individual variations in the conjugation profile, involving glucuronyltransferase isoforms such as UGT1A4 and UGT2B7 are respectively involved in the metabolism of anastrozole and letrozole (41)(42)(43). Glucuronidation profile by UGT1A4 was correlated to therapeutic efficacy of anastrozole in women with breast cancer (44).…”