Chlorpromazine inhibition of melatonin metabolism by normal and induced rat liver microsomes.

Hepatic metabolism of melatonin has been investigated. Melatonin was converted in vitro by rat liver microsomes to 6-hydroxymelatonin and to a lesser extent to N-acetylserotonin. Induction with phenobarbitone caused a fourfold increase in the formation of the minor product with little effect on 6-hydroxymelatonin production or melatonin turnover. In contrast, benzpyrene induction caused a dramatic increase in melatonin turnover but the formation of both metabolites, particularly 6-hydroxymelatonin was significantly reduced. This suggests that an alternative inducible pathway is involved in melatonin catabolism. Chlorpromazine, which elevates plasma melatonin in man and rat, significantly reduced melatonin turnover and reduced the formation of both metabolites in control and phenobarbitone induced microsomes. With benzpyrene induction, chlorpromazine inhibited melatonin turnover but in this group, 6-hydroxymelatonin concentrations were higher than controls. It is thus proposed that the drug preferentially inhibits the alternative benzpyrene inducible isozyme rather than the melatonin hydroxylase.