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 carcinogenicity. In addition, the compound has been clearly shown to be mutagenic 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 enzymes). The method used in addressing this problem relied on a new technique for monitoring clastogenesis in vivo, i.e., the acridine orange micronucleus assay method originally exploited by Hayashi et al. [1990]. The result of our experiments confirmed monocrotaline to be an effective clastogen in vivo, using the acridine orange method of assessment. The peak in induction of micronuclei occurred on the second day following intraperitoneal administration of the drug. Administration of phenobarbital prior to monocrotaline did appear to modulate the micronucleus induction. At 30 mg/kg bw monocrotaline, the pretreatment with phenobarbital appears to increase the intensity of monocrotaline clastogenesis, while the effect at higher doses (60 and 125 mg/kg bw) is a reduction in potency, presumably reflecting increased importance of Phase II metabolism for monocrotaline at these doses. Thus the study reported here confirms the potent in vivo clastogenesis of monocrotaline, and provides evidence for a dose-related shift in mechanism for the phenomenon.