CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes

Hirokun Nakamura, N. Ariyoshi, K. Okada, H. Nakasa, K. Nakazawa, M. Kitada

Research output: Contribution to journalReview articlepeer-review

35 Citations (Scopus)


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 6β-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 6β-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.

Original languageEnglish
Pages (from-to)469-480
Number of pages12
JournalCurrent Drug Metabolism
Issue number5
Publication statusPublished - Oct 2005
Externally publishedYes


  • CYP1A1
  • CYP3A4
  • Granisetron
  • Human liver microsomes
  • Metabolism

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry


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