Effect of cytochrome P-450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female mice

The studies presented were designed to investigate the effects of cytochrome P450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female B6C3F(1) mice. Groups of female B6C3F(1) mice were exposed to dynamic atmospheres containing tetrahydrofuran (THF) concentrations of 0, 5,400 or 15,000 mg/m(3) for 6 h per day, for 5 consecutive days. One-half of the animals in each THF exposure group were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) at 100 mg/kg (i.p.) 1 h before the start of each THF exposure period. Treatment with THF at 15,000 mg/m(3) caused marked microsomal enzyme induction in the liver. The cytochrome P450 content was nearly doubled (+98%), pentoxyresorufin-O-depentylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities were increased by 600% and 160%, respectively. ABT pretreatment effectively blocked microsomal enzyme induction at 15,000 mg/m(3). THF exposure had no effect on the subcellular morphology of hepatocytes, whereas ABT-pretreatment caused centrilobular fatty change. THF at 15,000 mg/m(3) caused increased cell proliferation in zone 3 (central vein region) of the liver (according to Rappaport), as indicated by a significantly higher PCNA (Proliferating Cell Nuclear Antigen) labelling index, but there were no effects at 5,400 ppm. ABT pretreatment prior to THF exposure at 15,000 mg/m(3) caused an exacerbated proliferative response of mouse liver, significantly higher PCNA labelling indices being observed in zones 2 (midzonal region) and 3. The exacerbated proliferative response of mouse liver under conditions of inhibited THF metabolism suggests that the mitogenic effects are related to prevailing THF tissue concentrations and not to the generation of THF oxidative metabolite(s).