The primary goal has been the elucidation of the structures of reactive metabolites responsible for the carcinogenic, cytotoxic and mutagenic activity of drugs, polycyclic aromatic hydrocarbons, and other environmental chemicals. The approach taken consists of: i) synthesis of primary and secondary oxidative metabolites, ii) study of the metabolism of the chemicals with liver microsomes and with purified cytochromes P450 and epoxide hydrolase, iii) evaluation of the mutagenicity and tumorigenicity of the synthetic metabolites, iv) elucidation of the roles of the cytochrome P450 system and epoxide hydrolase in modulating the mutagenicity of these metabolites, v) determination of the rates and products of reactions of arene oxides and diol epoxides with biopolymers and model compounds, and vi) search for agents capable of preventing the tumorigenicity of reactive metabolites. Synthetic studies have now made available optically pure arene oxide as well as cis and trans dihydrodiols at the 5,6-position of the environmental carcinogen quinoline. P. putida (UV4) forms the cis-(5R, 6S)-dihydrodiol while liver microsomes form highly optically enriched (5R, 6S)-oxide and (5R, 6S)-dihydrodiol on metabolism of quinoline. Acid-catalyzed solvolysis studies of substituted benz[a]anthracene 5,6-oxides as well as theoretical calculations (molecular mechanics by PCMODEL-PI and ab initio by GAUSSIAN 86 and 88 programs) of carbocation stability indicate the importance of steric factors in determining relative reactivity. These data are to be used in evaluation of the mechanism(s) by which microsomal epoxide hydrolase detoxifies such toxic and mutagenic substrates. We have recently proposed an empirical rule for prediction from CD spectra of absolute configuration of nucleoside adducts formed by reaction of the exocyclic amino groups of purine bases at the benzylic epoxide carbon of bay-region diol epoxides. Application of this rule has allowed correction of the assignment of configuration for two benzo[a]pyrene 7,8-diol 9,10-epoxide adducts previously misassigned. Solvolytic studies of the noncarcinogenic DE-1 and carcinogenic DE-2 diastereomers of benzo[a]pyrene 7,8-diol 9,10-epoxides suggest differences in their mechanism of reaction with biochemical nucleophiles at neutral pH (carbocation capture vs nucleophilic attack on neutral epoxide, respectively).
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