In vitro benzo[a]pyrene metabolism from lindane-treated rat liver: effect of oral and acute administration, and comparison with phenobarbital and methylcholanthrene pretreatment.

Lindane (γ-hexachlorocyclohexane) was given orally to Sprague-Dawley male rats in their basal diet, at 24, 120, and 240 ppm, for 4 weeks. Acute intoxication was obtained with ip injection, at 20 mg/kg/day for 3 consecutive days, and the inductive effect was compared to phenobarbital (ip, 80 mg/kg/day for 3 days) and methylcholanthrene (ip, 20 mg/kg/day for 3 days) pretreatment. The spectrofluorometric measurement of arylhydrocarbon hydroxylase (AHH) activity did not show any induction after lindane and phenobarbital pretreatment, while the quantitative determination of benzo[a]pyrene (BP) metabolites by thin-layer chromatography indicated an increase of 3-hydroxy-BP (3-OH-BP). Differences in the BP/protein ratio could explain this discrepancy. Consequently, lindane appeared as a weaker inducer of AHH activity than phenobarbital. The in vitro binding of [¹⁴C]BP metabolites to DNA was largely enhanced by the oral administration of lindane from as low as 24 ppm in the diet and seemed dose related until 120 ppm, reaching two or three times the control value. The acute intoxication by lindane resulted in an increase in BP metabolite binding to DNA similar to that obtained with 120 ppm in the diet. From the chromatographic pattern of BP metabolites, it is concluded that lindane induced a large formation of 4,5-BP-dihydrodiol, which was related to a two-fold increase in epoxide-hydratase activity. From these results, lindane could be considered as a phenobarbital-like inducer.