MECHANISM OF CARCINOGENESIS OF DIBENZ ACRIDINE

多环芳烃（PAHs）及其偶氮类似物(aza-

Polycyclic aromatic hydrocarbons (PAHs) and their aza-analogs (aza- PAHs) are ubiquitous environmental carcinogens. PAHs are known to require metabolic activation to their bay-region diol epoxides for producing their carcinogenic effects, but only recent evidence has implicated the bay-region diol epoxides with R,S,S,R absolute configuration as the ultimate carcinogens of several PAHs including benzo(a)pyrene (BP). However, the matter is not yet settled. Recent studies have indicated that many potentially carcinogenic PAHs and aza-PAHs may differ from BP in two aspects: (i) the absolute configuration of the bay-region diol epoxide of certain PAHs, such as dibenz(a,j)anthracene and its 14-aza-analog dibenz(c,h)acridine, may not play a major a major role in determining their tumorigenicity and (ii) certain PAHs, such as dibenz(a,h)anthracene, 7-methylbenz(a)anthracene and 7,12- dimethylbenz(a)anthracene may not be metabolized to their respec- tive R,S,S,R -bay-region diol epoxides with a high degree of stereoselectivity. In both the aspects, we believe that steric factors such as steric constraint in the bay-region, molecular shape and/or the presence of certain substituents (e.g. methyl or aza) play a significant role. In order to better understand the molecular factors (including steric ones) that may influence (i) the tumorigenic and mutagenic activities of the bay-region diol epoxide enantiomers, and (ii) the stereoselectivity of the enzymes involved in the metabolic activation of PAHs and aza-PAHs, we propose to study dibenz(a,h)acridine DB(a,h)ACR as a model compound, and compare our results with those obtained previously with other PAHs and aza-PAHs. DB(a,h)ACR differs from previously studied dibenz(c,h)-acridine in its molecular shape and in the degree of steric constraint in the bay-region. The specific aims of the proposed research are: (i) to synthesize enantiomerically pure DB(a,h)ACR-10,11-diols and their epoxides, (ii) to determine the stereoselectivity involved in the metabolism of DB(a,h)ACR and its enantiomerically pure DB(a,h)ACR-10,11-diols to DB(a,h)ACR-10,11-diols and DB(a,h)ACR-10,11-diol-8,9-epoxides, respectively by liver microsomes from control, 3-MC-treated and PB- treated rats, and by a purified and reconstituted cytochrome P-450c system, (iii) to assess the mutagenic and tumorigenic activities of DB(a,h)ACR and its enantiomerically pure dihydrodiol and diol epoxide derivatives, and (iv) to evaluate the stereochemical model proposed by Jerina et al. for the PAH binding site of cytochrome P-450c.