METABOLISM OF NONYLPHENOL BY RAT AND HUMAN MICROSOMES

The in vitro metabolism of [C-14]-nonylphenols (NPs) by rat hepatic mi crosomes in vitro was examined. Product formation was NADPH dependent and inhibited by the cytochrome P450 inhibitors, piperonyl butoxide an d SKF525. Hepatic microsomes isolated from various inducer-treated rat s (including beta naphthoflavone, phenobarbital, ethanol, dexamethason e, and clofibrate which selectively induce CYP1A, 2B, 2E, 3A and 4A, r espectively) all metabolized NPs. Only microsomes from phenobarbital-t reated rats exhibited a significantly higher activity towards NPs and showed a different profile of NP metabolites compared to control, untr eated rats. Microsomes from human CYP2B6 transfected cells with endoge nous NADPH-P450 reductase activity but not microsomes from the non-tra nsfected parent cells metabolized NPs. The metabolism of NPs using mic rosomes from phenobarbital-treated rats was inhibited by 4-amino-2, 6- dinitro-1-t-butylxylene, a specific CYP2B enzyme inhibitor. Addition o f a general anti-CYP2B sera to the reaction mixture attenuated the enz yme activity of microsomes from phenobarbital-treated rats to metaboli ze NPs. This metabolic reaction was, however, insensitive to a specifi c anti-CYP2B1 sera that had been shown to inhibit enzyme activities at tributed only to CYP2B1 suggesting that the CYP2B2 pathway is predomin ant in NP metabolism. The results indicate that hepatic cytochrome P45 0 enzyme(s) can metabolize NPs and that CYP2B isozymes are probably in volved. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.