Cytochrome P450-mediated activation and toxicity of chlorpyrifos in male and female rats.

This study compared CYP-mediated activation and toxicity of chlorpyrifos (CPF) in male and female rats, since gender difference in CPF toxicity in rats has been reported. A dose of 50 mg/kg of CPF in corn oil was administered ip to 2 groups of male and female rats while the respective control groups received the vehicle alone. Measurement of cholinesterase activity in brain showed no difference in cholinesterase inhibition between male and female rats 3 h following CPF administration. In contrast, inhibition of plasma cholinesterase was significantly greater in females than males. The activities of microsomal CYP 1A1, 2B1, 2E1 and 3AV 2 determined whether CPF, a suicide substrate of cytochrome P450 enzymes, was metabolized by the liver CYP enzymes. The CYP 1A1 and 2B1 activities were significantly decreased in both male and female rats, with the CYP 1A1 decrease in females markedly greater than that in males. CPF produced a significant inhibition of only CYP 3A1/2 activity, but not CYP 2E1 activity, irrespective of gender effect. These results demonstrated that CYP 1A1, 2B1 and 3A1/2 were differentially involved in the metabolism of CPF to CPF-oxon in both genders and the extent of plasma cholinesterase inhibition was significantly greater in female than male rats.

Effect of cytochrome P450 inducers on the metabolism and toxicity of thiram in rats.

Thiram is a dithiocarbamate compound widely used as an agricultural fungicide. This study examined the effect of cytochrome P450 (CYP) inducers on the metabolism and toxicity of thiram in rats. Rats were pretreated with 3-methyl cholathrene (3-MC), phenobarbital (PB), isoniazid (INH), or pregnenolone-16a-carbonitrile (PCN) as selective inducers of CYP 1A1, 2B1, 2E1 and 3A2, respectively. Thiram was administered ip to induced rats at 0.1 or 0.5 mmol/kg, and the animals were sacrificed 3 or 24 h later to assess P450 interaction and liver damage, respectively. No significant inhibition of 3-me-induced CYP1A1 was observed with either thiram dose at 3 or 24 h after treatment; similar results were noted for rats induced with PB or PCN. By contrast, when INH was the selective inducer of CYP2E1, there was significant inhibition by thiram 3 h and 24 h after treatment, suggesting that thiram was metabolized by the induced CYP2E1; there was a significant increase in ALT activity reflective of liver damage in the rats treated with thiram. The results suggest that CYP2EI induced by INH may be significantly involved in the metabolism of thiram, and the associated liver damage.