Theoretical Study On Cytochrome P450 Mediated Metabolism Of Aromatic Compounds

Aromatic compound is one of the most typical organic pollutants in our environment because of it's extensive distribution.The structure of it includes one benzene ring at least which is mutagenic,carcinogenic and teratogenic and posing a serious threat to human health when these coupound enter the human body.Cytochrome P450 monooxygenases,one of the most versatile enzymes of nature,paly major roles in the metabolism(metabolic detoxification and activation)of xenbiotics.Aromatic compounds are activated into electrophilic forms to react irreversibly with nucleophiles,such as DNA,RNA and proteins,whch could trigger cancer.Therefore,it is essential to know the underlying mechanisms of these compounds' metabolism initiated by CYP450.However,sometimes it is difficult to do these researches by traditional experimental methods.To resolve this conundrum,we have investigate a varievy of reaction pathways based on density functional theory(DFT)methods.The main conclusions are as follows:(1)Ipso-substitution is a novel pathway of the cytochrome P450-catalyzed conversion of p-subsituted phenols,but seldom scientists have studied the underlying mechanism of it based on the methods of quantum chemistry calculation.We have investigated the pathways of ipso-substitution and oxygen addition-elimination mechanism of Bisphenol A with DFT methods.Comparing two kinds of pathways,we find that the way of ipso-substitution is the better way:the activate site of P450 abstract hydrogen from the phenol directly,and then the hydroxyl rebound to the o-position or p-position.This reaction only occurs in low-spin state.The rate-determining step is the hydrogen extraction.Then we studied a series of p-subsituted phenols to find that the substituents effects is closely related to the average energy of this reaction�the energy trends to increasing along with the Hammett constant ?p.(2)Benzo[a]pyrene,as one of the most typical substrates of the CYP450,has a strong carcinogenic.We have compared all of the pathways of it's active sites that were metabolized by CYP450 in the aspects of reaction kinetics and thermodynamics.And we have further explained the phenomenon of regioselectivity.Lastly,we analysised the pathway of the production of 9,10-epoxy BaP and gave the conculsion that this product maybe only occur in low-spin states.(3)Aromatic amine derivatives can be metalized by P450 enzymes(P450s)to form active electrophilic compounds,which will potentially react with nucleophilic DNA and protein to exert their carcinogenic effect.We calculated the activation energy barriers(AE)of hydrogen abstraction for 28 aniline derived substrates with state-of-the-art density functional theory(DFT)methods.And find that the bond dissociation energy for N-H(BDEN-H)possesses good linearity with ?E*.Therefore,successful models of good predictability for P450s N-hydroxylation were built,with the pre classification of these diverse substrates into aromatic(R2 = 0.92)and heteroaromatic amines groups(R2 = 0.95).This study has provided the basis for predicting the metabolic activity and even the risk of potentially carcinogenic of these compounds.