Effect of common exon variant (p.P364L) on drug glucuronidation by the human UDP-glucuronosyltransferase 1 family.

The UDP-glucuronosyltransferases (UGTs) comprise a major excretion pathway for diverse endogenous and exogenous substrates. Relations are reported between polymorphisms of exon 1 of UGT1 and drug side effects or carcinogenesis, but few studies exist of common exon polymorphisms that exert influence throughout UGT1 isoforms. We analysed the polymorphism c.1091C>T, resulting in the amino acid substitution of p.P364L, found on common exon 4. We studied 187 healthy, adult Japanese volunteers. The allele frequency was 0.0053. We investigated the effect of p.P364L on glucuronidation of β-estradiol, acetaminophen, propofol, lamotrigine, imipramine and cyproheptadine in an in vitro expression study. The V(max) values for β-estradiol of p.P364L-UGT1A1, 1A3, 1A7, 1A8 and 1A10 were 36.6%, 82.1%, 26.8%, 29.2% and 22.5%, respectively, of the corresponding wild-type. Glucuronidation activity towards acetaminophen of p.P364L-UGT1A1, 1A6, 1A7, 1A8, 1A9 and 1A10 was 50.3%, 46.4%, 17.2%, 44.1%, 5.0% and 42.8%, respectively, of wild-type. Glucuronidation activity towards propofol of p.P364L-UGT1A7, 1A8, 1A9 and 1A10 was 44.0%, 49.8%, 29.0% and 71.1%, respectively, of wild-type. Substrate inhibition was observed in lamotrigine, cyproheptadine and imipramine glucuronidation by wild-type UGT1A4 but vanished for p.P364L. The presence of p.P364L near the UDP-glucuronic acid binding site could lead to extensive reduction of enzyme activity of many UGT1s. Our results suggest that p.P364L is an important mutation that could give rise to adverse effects of various drugs, or carcinogenesis. It is important to study common exon mutations because these can reduce activity of all UGT1 isoforms.