Predictive value of comparative molecular field analysis modelling of naphthalene inhibition of human CYP2A6 and mouse CYP2A5 enzymes

The objects of this study were first to compare how well the recently constructed structure-inhibition activity relationship models of mouse CYP2A5 and human CYP2A6 predict the interaction of naphthalene in liver microsomes and secondly to study if these CYP enzymes actually oxidize naphthalene. The CoMFA model of CYP2A5 predicted the IC50 value of naphthalene to be 42 muM (18-115 muM 95% CL) whereas in the in vitro experiment the result was 74 muM (65-83 muM) with the corresponding values for CYP2A6 being 41 muM (18-112 muM) and 25 muM (21-30 muM), respectively. Naphthalene appeared to be a competitive inhibitor both for mouse and human liver microsomal coumarin 7-hydroxylase, which is the specific probe activity for CYP2A5 and CYP2A6. The K-i-value for the mouse enzyme was between 12-26 muM and for the human enzyme 1.2-5.6 muM. A 1-h in vitro incubation of naphthalene with human and pyrazole treated mouse liver microsomes produced more 1-naphthol than 2-naphthol. Antibody against the purified CYP2A5 inhibited 50-60% of the formation of 1-naphthol and 30-40% of the formation of 2-naphthol. These results indicate that in silico CoMFA models predict relatively well the interaction of naphthalene with CYP2A5 and CYP2A6 and that these CYPs actually oxidize naphthalene in vitro. CoMFA CYP2A5 and CYP2A6 models are thus useful as a technique for elucidating the interaction and potency of untested chemicals with these CYPs. (C) 2003 Elsevier Ltd. All rights reserved.