Indole-3-carbinol modulation of hepatic monooxygenases CYP1A1, CYP1A2 and FMO1 in guinea pig, mouse and rabbit

Abstract

Indole-3-carbinol (I3C), a major component of cruciferous vegetables, has been shown to be chemoprotective against cancer in a number of animal models and is being evaluated as a potential agent to prevent breast cancer in healthy women. Some concern has been raised related to the long-term use of I3C, as in some models chronic dietary post-initiation exposures promote cancers. I3C administration to rats marked induces several cytochrome P450s (CYPs), especially CYP1A1 (approx. 25-fold), while at the same time inhibiting the expression of FMO1. The consequence is a marked shift in the metabolic profile of drugs such as nicotine and tamoxifen, that are substrates for both monooxygenases. Such an effect could lead to adverse drug reactions in humans. In order to determine if the effect of I3C was manifest in species other than the rat, we fed 2000-ppm I3C to male guinea pigs, mice and rabbits for a period of 4 weeks. In each species, induction of CYP1A1/1A2 expression was observed in the liver but little or no effect on FMO1 was evident, with the possible exception of the rabbit. These data demonstrate that the ability of I3C to both induce CYP1A1 and inhibit FMO1, as observed in the rat, may not be common to other mammals for which FMO1 is the major isoform in the liver.