MICRONUCLEI IN MICE TREATED WITH MONOCROTALINE WITH AND WITHOUT PHENOBARBITAL PRETREATMENT

Monocrotaline is a very potent toxin, producing significant effects of pneumotoxicity, hepatotoxicity, and teratogenicity, as well as carcin ogenicity. In addition, the compound has been clearly shown to be muta genic after metabolic activation. The goal of the experiments reported here was to confirm the reported clastogenesis induced by this agent in vivo and to evaluate the impact of modulation of metabolic activity by phenobarbital, a potent P-450 inducer (both Phase I and Phase II e nzymes). The method used in addressing this problem relied on a new te chnique For monitoring clastogenesis in vivo, i.e., the acridine orang e micronucleus assay method originally exploited by Hoyashi et al. [19 90]. The result of our experiments confirmed monocrotaline to be an ef fective clastogen in vivo, using the acridine orange method of assessm ent. The peak in induction of micronuclei occurred on the second day f ollowing intraperitoneal administration of the drug. Administration of phenobarbital prior to monocrotaline did appear to modulate the micro nucleus induction. At 30 mg/kg bw monocrotaline, the pretreatment with phenobarbital appears to increase the intensity of monocrotaline clas togenesis, while the effect at higher doses (60 and 125 mg/kg bw) is a reduction in potency, presumably reflecting increased importance of P hase II metabolism for monocrotaline at these doses. Thus the Study re ported here confirms the potent in vivo clastogenesis of monocrotoline , and provides evidence for a dose-related shift in mechanism for the phenomenon. (C) 1995 Wiley-Liss, Inc.