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, COCH3, COPh, COOH, F, Cl, and Br) were incubated with rat liver microsomes, the substituent was eliminated to produce hydroquinone, and the reaction was inhibited by CO and a cytochrome P450-specific inhibitor. In the case of p-cresol (substituent = CH3), p-toluquinol was formed instead of hydroquinone. Experiments using 18O2 proved that the elimination is accompanied with ipso-substitution by the oxygen atom of the active species in cytochrome P450. These results are similar to those in a cytochrome P450. These results are similar to those in a cytochrome P450 chemical model system (Ohe, T., et al., Tetrahedron Lett. 42, 7681-7684, 1995), implying that the model is a good mimic of cytochrome P450. Substrates that lack a hydroxy group, namely p-substituted toluenes, did not undergo the reaction, thus indicating that a hydroxy group at the p-position to the eliminated substituent is necessary for this pathway. This is the same as the result obtained with the cytochrome P450 model. Finally, to elucidate how the substituent is eliminated, we attempted to detect the product derived from the eliminated group with several substrates. Results indicated that the mechanism of the substituent elimination can be divided into two types: the substituent is eliminated as an anion or as a cation.
Ohe
T
T
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Mashino
T
T
Hirobe
M
M
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010103:Oxygen Isotopes; D010636:Phenols / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D010103:Oxygen Isotopes; D010636:Phenols; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D008797:Metyrapone