title: CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes.
abstract: Granisetron, a potent 5-HT3 receptor antagonist, has been reported to be mainly metabolized to 7-hydroxygranisetron and a lesser extent to 9'-desmethylgranisetron in humans. A previous study indicated that cytochrome P450 (CYP)3A4 is a major catalyst of 9'-demethylation, although the major CYP isoform(s) responsible for 7-hydroxylation are unknown. To clarify granisetron 7-hydroxylase, the in vitro metabolism of granisetron using expressed human CYPs and human liver microsomes was investigated. 7-Hydroxygranisetron was produced almost exclusively by CYP1A1, while, apparently, 9'-desmethylgranisetron was preferentially produced by CYP3A4. Marked inter-individual differences in the ratio of the formation of 7-hydroxygranisetron and 9'-desmethylgranisetron in human liver microsomes was observed. Granisetron 7-hydroxylase activity was strongly correlated with benzo[a]pyrene 3-hydroxylase activity (p<0.0001), but not with testosterone 6beta-hydroxylase activity in human liver microsomes. Furthermore, an anti-human CYP1A1 antibody completely inhibited 7-hydroxylation in human liver microsomes, however, the reaction was not inhibited at all by an anti-CYP3A4 antibody. On the other hand, granisetron 9'-demethylase activity correlated significantly not only with testosterone 6beta-hydroxylase activity (p<0.0001) but also with benzo[a]pyrene 3-hydroxylase activity (p<0.01). Consistent with this, both the anti-CYP1A1 and anti-human CYP3A4 antibodies inhibited the 9'-demethylase activity. These data indicate that CYP1A1 is a major enzyme responsible for the metabolism of granisetron via a main 7-hydroxylation pathway and an alternative 9'-demethylation route. This is the first report demonstrating the substantial contribution of CYP1A1 to the metabolism of a drug, although its role in the metabolism of environmental compounds is well established.
authors.affiliation: Division of Pharmacy, University Hospital, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. hirokun@ho.chiba-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: N
authors.initials: N
authors.lastname: Ariyoshi
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: H
authors.initials: H
authors.lastname: Nakasa
authors.forename: K
authors.initials: K
authors.lastname: Nakazawa
authors.forename: M
authors.initials: M
authors.lastname: Kitada
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D017829:Granisetron / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007313:Insecta / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged
chemical_list: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D019138:Antibodies, Blocking; D001579:Benzopyrene Hydroxylase; D019363:Cytochrome P-450 CYP1A1; D017829:Granisetron; D007527:Isoenzymes