Interaction of tetrachloroethylene with rat hepatic microsomal P450-dependent monooxygenases

1. We have studied the effects of tetrachloroethylene (PCE) on the kinetics of the P450-dependent monooxygenases in rat liver microsomes. 2. 7-Pentoxyresorufin O-depentylase (PROD) and 7-benzyloxyresorufin O-debenzylase (BROD) activities in phenobarbital (PB)-treated rat liver microsomes were substantially inhibited by PCE. The inhibition profiles were non-competitive for both enzyme activities; Ki's from Eadie-Hofsee plots were 0.16 and 0.29 mM for PROD and BROD respectively. In contrast, the enzyme activities in untreated, beta-naphthoflavone (BNF)-, isoniazid (ISN)- and pregnenolone-16 alpha-carbonitrile (PCN)-induced microsomes were not affected by PCE. 3. 7-Ethoxycoumarin O-deethylase (ECOD) activity in PB-induced microsomes was competitively inhibited by PCE, with a Ki that was lower than those of other microsomes. 4. PCE inhibited 7-ethoxyresorufin O-deethylase (EROD) activities in some microsomes slightly. The Ki for PCE was the lowest in untreated, followed by ISN-treated microsomes. 5. No effect of PCE upon aniline 4-hydroxylase (AN4H) and testosterone 6 beta-hydroxylase (TS6BH) activities was evident in any microsomal preparation. 6. These results indicate that PCE inhibits PB-inducible, P450-dependent monooxygenases in vitro non-competitively or competitively, and that the P450 enzymes of the P4502B subfamily may contribute to PCE toxicity.