Carcinogenic Metabolic Activation And Carcinogenic Mechanisms Of Naphthalene By The Cytochrome P450 Enzyme

As a kind of oraanic pollutant,polycyclic aromatic hydrocarbons(PAHs)migrate.transform and enrich in the environment,which w ill cause cancer health risk after being absorbed by human body.Metabolic activation and metabolic mechanism of strong carcinogenic macrocyclic PAHs represented by benzo[a]pyrene have been paid much attention and explored.The work of weak carcinogenic small cyclic PAHs represented by naphthalene also needs further investigate to be understood.Namely,naphthalene's carcinogenic activation pathways at the molecular level ought to be explored to find the molecular basis of its probable carcinogenicity.Based on the QM/MM and DFT methods of computational chemistry,this work mainly studied the metabolic activation of naphthalene by cytochrome P450 enzymes that widely existing in human body.screened its initial metabolic activation sites,then inquired into the transformation of its carcinogenic activation metabolic intermediate,and finally analyzed the interaction between its ultimate carcinogen and DNA base molecule to explore the carcinogenic mechanism.The main contents and problems solved of the study include:firstly,the selectivity of additive target(C? and C?)in the complex structure of naphthalene and CYP 1B1 under 15 conformations was studied after molecular dynamics,the C? site is competitive with the C? site which is traditionally considered to be more active,and the average potential barrier of the former is lower than that of the latter by 2.6 kcal·mol-1.Thus,the spatial structure and reaction environment of the enzyme system should be considered in the study of the activation of pollutant by enzymes.Secondly,the intermediate of naphthalene in process of metabolism and activation,1,2-naphthalene epoxide,is extremely unstable,and can be rapidly transformed under the action of hydrogen ion,hydroxyl ion and hydroxyl radical respectively,which produces 1,2-dihydro-1,2-naphthalenediol and 1,2-naphthol respectively,then them will may produce the ultimate carcinogen 1.2-naphthoquinone.Thirdly,the work identified the dominant addition site of guanine is N7 after 1,2-naphthoquinone attack to it.The ensuing electrophilic addition reaction to forming the final covalent conjugate 1,2-naphthol-N7-guanine was analyzed.It was found that the potential barriers of the six-part reaction to form 1,2-naphtiol-N7-guanine are 16.0?30.0 kcal·mol-1,which indicates the yield of the process of interaction between them is low.Based on these.I have probably completed the research on the whole activation process of naphthalene and its interaction with the base molecule of DNA,which provides some help for us to explore the carcinogenicity of naphthalene and other PAHs at the molecular level.Firstly,the selection of activation addition targets and the transformation of carcinogenic activation intermediate in the initial metabolic activation process of naphthalene may also exist in other small-cyclic and macrocyclic PAHs.Secondly,the interaction between the possible ultimate carcinogen of naphthalene and bases in DNA.and the formation of covalent conjugates offer an insight into the mechanism of the weak carcinogenicity of naphthalene.Thirdly.naphthalene is metabolized in a complex enzyme environment to produce carcinogenicity alter it's activated by different P450 enzymes combining with experimental data.In a word,this computational study provides the analysis and insight of computational chemistry and predictive toxicology for the carcinogenicity of naphthalene,and to some extent,exhibits the theoretical support for the follow-up study.