Journal of pharmacobio-dynamics 1986-09-01

Mechanism of potentiation of BPMC toxicity by fenthion pretreatment in mice.

T Miyaoka, S Tsuda, Y Shirasu

Index: J. Pharmacobiodyn. 9(9) , 697-703, (1986)

Full Text: HTML

Abstract

The mechanism of potentiation of 2-sec-butylphenyl N-methylcarbamate (BPMC) toxicity by O,O-dimethyl O-(3-methyl-4-methylthiophenyl) phosphorothioate (fenthion) in mice was investigated in relation to BPMC metabolism in the liver. Simultaneous administration of BPMC and either one of the thiophosphates (fenthion, its sulfoxide and sulfone) in a dose of 1/40 of its LD50 resulted in a 2- to 3-fold potentiation. On the other hand, one hour pretreatment with these thiophosphates in the same dose resulted in a 7- to 9-fold potentiation of BPMC toxicity, but that with fenthion oxon resulted in only a 2-fold potentiation. Plasma levels of BPMC were significantly increased by pretreatment with the thiophosphates, but not by the oxon. In an in vitro study, an inhibition of hepatic microsomal metabolism of BPMC and a decrease of cytochrome P-450 content by thiophosphates were observed at the concentration of 10 microM, but not by 25 microM of oxon. In an in vivo study, an inhibition of hepatic microsomal metabolism of BPMC, aminopyrine and aniline by the thiophosphates pretreatment were observed in doses of 1/40 of their LD50's, but not by the oxon in doses of up to 4/10 of its LD50. Cytochrome P-450 content was decreased by the thiophosphates in doses of 4/10 of their LD50's, but not by the oxon. These results suggested that the inhibition of BPMC metabolism might be, at least in part, the mechanism for the fenthion-induced potentiation of BPMC toxicity and that desulfuration of fenthion might be responsible for the inhibition of BPMC metabolism.