Faculty Bibliography

The relationship between microsomal dimethylnitrosamine (DMN) demethylase activity and the capacity of isolated hepatic microsomes to activate DMN to a mutagen was examined using microsomes from C57 and DBA/2 mice which had been exposed to three different types of microsomal enzyme inducers: phenobarbital, which induces cytochrome P-450, 3-methylcholanthrene, which induces cytochrome P-448, and the polychlorinated biphenyl, Aroclor 1254 which appears to induce both types of cytochromes. DNM induced mutagenesis was assayed by a Salmonella auxotroph reversion test. With the C57 mice all three inducers increased both the activity of microsomal DMN demethylase and the capacity of the microsomes to activate DMN mutagenicity. In each case, however, the increase in mutagenicity was disproportionately greater than the increase in DMN demethylase activity. This was particularly evident with microsomes prepared from Aroclor induced mice. Microsomes from 3-methylcholanthrene treated DBA/2 mice were not induced for DMN demethylase or the activation of DMN mutagenicity. In addition the capacity of Aroclor to function as an inducer was relatively poor in this strain. Both DMN demethylation and mutagenesis were inhibited by the addition of either SKF 525-A or benzo (a)pyrene to the reaction mixtures. Thus microsomal activation of DMN to a mutagen and DMN demethylase appear to involve both cytochromes P-450 and P-448.

The mutagenic effects of vinyl chloride (VC) on Salmonella typhimurium strain TA1530 are enhanced by mouse or rat liver extracts. The extracts prepared from mice pretreated either with vinyl chloride or the microsomal enzyme inducer, Aroclor 1254, did not produce any greater stimulation of VC-dependent mutagenesis than extracts from untreated animals. These same extracts, however, differed markedly in their capacity to stimulate the mutagenicity of dimethylnitrosamine (DMN), a compound which is converted to a mutagen by an NADPH dependent microsomal mixed function oxidase. The order of activity of the extracts with DMN was Aroclor pretreated is greater than untreated is greater than VC pretreated. Furthermore, the stimulatory effect of the liver extracts on VC mediated mutagenesis did not require NADPH and was still evident in liver extracts in which the microsomal mixed function oxidase system had been heat inactivated. The mutagenic activity of VC also was found to be stimulated by riboflavin in the presence of light suggesting that free radicals may be involved in VC dependent mutagenesis.

Reactions of thioethers (sulfides) with excited triplet benzophenones have been studied (1) by retardation by the sulfides of photoreduction by isoborneol, (2) by quenching by naphthalene of photoreduction by the sul-fides, and (3) by quenching of phosphorescence of the ketone by the sulfides. Quenching rate constants, fer, are in the range 10⁷-10⁹ M ^_1 sec^-1. They are highest for aliphatic and lowest for aromatic sulfides, and values are de-creased by a branching and by electronegative substituents, and higher in acetonitrile than in benzene. Benzophenone is photoreduced by sulfides containing a H. Quantum yields are low, Ï„~ 0.05-0.2, and increase with decreasing values of kir,. Quenching of phosphorescence of benzophenone by mercaptans shows values of kq in the range 10⁷-10⁹ M-^l sec^-1, highest for aromatic, lowest for aliphatic thiols, decreased by electron-attracting substituents. Reversible hydrogen abstraction is not important in reactions of sulfides, while probably dominant in reactions of thiols. Quenching and photoreduction by sulfides may proceed via a common charge transfer complex, in which a full unit of charge separation is not developed. Contributions of charge transfer, hydrogen transfer, and polarizability in quenching and reduction of excited carbonyl compounds by alcohols, ethers, amines, sulfides, and mercaptans are discussed. © 1973, American Chemical Society. All rights reserved.