CARCINOGENIC polycyclic hydrocarbons such as the widespread environmental contaminant, benzo(a)pyrene (Fig. 1a), undoubtedly require metabolic activitation. Boyland1 proposed that epoxides, whose formation is catalysed by the NADPH-dependent microsomal mono-oxygenases2,3, are the initial products of double-bond oxidation and we have suggested that epoxides are the important reactive metabolites responsible for the biological effects of these carcinogens4.

Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide

Publisher Summary This chapter discusses the role of glutathione (GSH) and glutathione s-transferases in metabolism of chemical carcinogens and other electrophilic agents. GSH is a tripeptide (I) that is present in nearly all living cells and is the most abundant sulfhydryl compound present in animal tissues, mainly in the cytosol. The chapter illustrates the wide range of electrophilic agents, including several known mutagens and carcinogens, which conjugate with GSH, a process usually catalyzed by the GSH S-transferases. This conjugation is probably a protective mechanism and is the initial stage in mercapturic acid biosynthesis for the elimination of foreign compounds from the body. GSH S-transferases provide protection not only by catalyzing the conjugation of a potential toxicant with GSH, but also by preferentially binding, even covalently, that toxicant. The reactive electrophiles that conjugate with GSH also bind to DNA, RNA, and protein and identification of GSH conjugates provide information on the nature of these biologically active intermediates or even their immediate precursors. Thus, the knowledge of the way in which mutagens and carcinogens are metabolized is essential to a better understanding of their mode of action and of the processes for their detoxication.

The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents.

https://science.sciencemag.org/content/sci/185/4151/573.full.pdf

Arene oxides: a new aspect of drug metabolism.

https://cancerres.aacrjournals.org/content/canres/38/6/1479.full.pdf

Some Current Perspectives on Chemical Carcinogenesis in Humans and Experimental Animals: Presidential Address

1. Several aromatic and olefinic compounds are converted to intermediate arene and alkene oxides by mammalian mono-oxygenases. Intermediate arene oxides rearrange non-enzymically to phenols. Arene and alkene oxides are converted by epoxide hydrases to vicinal diols and by glutathione S-epoxide conjugases to glutathione conjugates. Due to their high electrophilic reactivity, such oxiranes also bind to proteins, RNA and DNA. Mutagenic, carcinogenic and cytotoxic effects of several aromatic and olefinic compounds appear to be due to the formation of intermediate epoxides and their reaction with tissue constituents. Whether a given aromatic or olefinic compound produces such an effect would thus depend on a variety of factors, such as the relative rate of formation and degradation of the intermediate oxirane, on its stability with respect to spontaneous isomerization to the corresponding phenol and on its chemical electrophilic reactivity.2. Epoxide hydrases, which convert such intermediate oxiranes t...

Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2874%2980420-5

Polycyclic hydrocarbon epoxides: the involvement of 8,9-dihydro-8,9-dihydroxybenz (a) anthracene 10,11-oxide in reactions with the DNA of benz (a) anthracene-treated hamster embryo cells.

The formation of "K-region" epoxides as hepatic microsomal metabolites of 7-methylbenz(a)anthracene and 7,12-dimethylbenz(a)anthracene and their 7-hydroxymethyl derivatives.

1. The oxidation of aromatic hydrocarbons to arene oxides and the reduction of these oxides to the parent hydrocarbons are both catalysed by enzymes in the microsomal fraction of rat liver. A suggested name for the enzyme concerned in the reduction of these epoxides is 'epoxide reductase'.2. 'Epoxide reductase' is NADPH-dependent and is inhibited by oxygen.3. Preliminary investigations suggest that the enzyme is specific for both 'K-region' and 'non-K-region' arene oxides.

Joan Booth

Papers

Polycyclic hydrocarbon epoxides: the involvement of 8,9-dihydro-8,9-dihydroxybenz (a) anthracene 10,11-oxide in reactions with the DNA of benz (a) anthracene-treated hamster embryo cells.

The formation of "K-region" epoxides as hepatic microsomal metabolites of 7-methylbenz(a)anthracene and 7,12-dimethylbenz(a)anthracene and their 7-hydroxymethyl derivatives.

Enzymic reduction of aromatic hydrocarbon epoxides by the microsomal fraction of rat liver.

Different pathways involved in the metabolism of the 7.8- and 9, 10-dihydrodiols of benzo(a)pyrene

Formation of glutathione conjugates as metabolites of 7,12-dimethylbenz-(a)anthracene by rat-liver homogenates.