SUBSTITUENT ELIMINATION FROM P-SUBSTITUTED PHENOLS BY CYTOCHROME-P450- IPSO-SUBSTITUTION BY THE OXYGEN-ATOM OF THE ACTIVE SPECIES

When various p-substituted phenols (substituent = NO2, CN, CH2OH, COCH 3, COPh, COOH, F, Cl, and Br) were incubated with rat liver microsomes , the substituent was eliminated to produce hydroquinone, and the reac tion was inhibited by CO and a cytochrome P450-specific inhibitor. In the case of rho-cresol (substituent = CH3), rho-toluquinol was formed instead of hydroquinone. Experiments using O-18(2) proved that the eli mination is accompanied with ipso-substitution by the oxygen atom of t he active species in cytochrome P450. These results are similar to tho se in a cytochrome P450 chemical model system (Ohe, T., et at, Tetrahe dron Left. 42, 7681-7684, 1995), implying that the model is a good mim ic of cytochrome P450. Substrates that lack a hydroxy group, namely p- substituted toluenes, did not undergo the reaction, thus indicating th at a hydroxy group at the p-position to the eliminated substituent is necessary for this pathway. This is the same as the result obtained wi th the cytochrome P450 model. Finally, to elucidate how the substituen t is eliminated, we attempted to detect the product derived from the e liminated group with several substrates. Results indicated that the me chanism of the substituent elimination can be divided into two types: the substituent is eliminated as an anion or as a cation.