UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation.
The UDP-glucuronosyltransferase (UGT) family plays a major role in the excretion of endobiotics and xenobiotics and their metabolites. Human UGT1A4 catalyzes the glucuronidation of primary, secondary, and tertiary amines, sapogenins, androgens, and progestins. We directly sequenced polymerase chain reaction-amplified fragments of the UGT1A4 gene from 100 healthy adult Japanese volunteers and calculated their mutation frequency. We identified four single nucleotide polymorphisms (SNPs): three in exon 1 (142T > G: L48V, 448T > C: L150L, 804G > A: P268P), and one in intron 1 (867 + 43C > T). We found three types of alleles with distinct SNP combinations that coded for different amino acid sequences: L48V-L150L-P268P-867 + 43C > T (frequency, 0.155), L48V (0.01), and P268P (0.01) (wild-type frequency was 0.825). The L48V mutant gave twice the efficiency (V(max)/K(m)) for the antipsychotic drug clozapine as the wild-type. Efficiencies of L48V for trans-androsterone, imipramine, and cyproheptadine were increased, but the efficiency for tigogenin was reduced. L48V therefore increased or decreased the glucuronidation activity, depending upon the substrates. This study shows the importance of identifying patients with the L48V polymorphism when calculating dosage, and when considering the potential adverse effects of drugs that are substrates of UGT1A4.
Mori
Asami
A
Department of Pediatrics, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan. asamim@belle.shiga-med.ac.jp
Maruo
Yoshihiro
Y
Iwai
Masaru
M
Sato
Hiroshi
H
Takeuchi
Yoshihiro
Y
D000483:Alleles; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D003024:Clozapine / Q000493:pharmacokinetics*; D017931:DNA Primers; D005787:Gene Frequency; D014644:Genetic Variation; D005822:Genetic Vectors; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D007564:Japan / Q000453:epidemiology; D007700:Kinetics; D011110:Polymorphism, Genetic / Q000235:genetics
D014150:Antipsychotic Agents; D017931:DNA Primers; D020719:Glucuronides; D007527:Isoenzymes; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase; D003024:Clozapine