The metabolism of 3-methylcholanthrene and some related compounds by rat-liver homogenates

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Abstract
A chromatographic investigation of the products of the metabolism of 3-methylcholanthrene by rat-liver homogenates showed the formation of compounds with the properties of 1- and 2-hydroxy-3-methylcholan-threne, cis- and trans-1, 2-dihydroxy-3-methylcholanthrene and 11-12-dihydro-11,12-dihydroxy-3-methylcholanthrene. A glutathione conjugate that is probably S-(ll-12-dihydro-12-hydroxy-3-methyl-ll-cholanthrenyl)glutathione was also detected. 3-Methylcholanthrene-l-and -2-one and -1, 2-quinone were also present, but these products may have arisen by the chemical oxidation of the corresponding hydroxy compounds. Other metabolic products were tentatively identified as 9- and 10-hydroxy-3-methylcholanthrene, 4, 5-dihydro-4, 5-dihydroxy-3-methylcholanthrene and 3-hydroxymethylcholanthrene. 1- and 2-Hydroxy-3-methylcholanthrene were converted by homogenates into the related ketones and into products with the properties of cis- and trans-1, 2-dihydroxy-3-methylcholanthrene; 3-methylcholanthrene-1- and -2-one were converted into their related hydroxy compounds and into the isomeric 1, 2-dihydroxy compounds. The isomeric 1, 2-dihydroxy compounds were each partly converted into the other isomer by these homogenates. All the above substrates also yielded products that appeared to be derivatives of 3-hydroxymethylcholanthrene. 3-Methyl-cholanthrylene was converted by rat-liver homogenates into products with the properties of trans-1, 2-dihydroxy-3-methylcholanthrene, 2-hydroxy-3-methycholanthrene and 3-methylcholantrene-2-one. A small amount of the cis-1, 2-dihydroxy compound was also formed, together with a glutathione conjugate that is possibly S-(2-hydroxy-3-methyl-l-cholanthrenyl)glutathione or its positional isomer. An unidentified product was detected in the metabolism of 3-methylcholanthrene, the monohydroxy compounds, the ketones and the dihydroxy compounds, the formation of which appeared to involve metabolism at the 1, 2-bond. 11.12-Epoxy-11, 12-dihydro-3-methylcholanthrene was converted by rat-liver homogenates into products with the properties of 11-hydroxy-3-methylcholanthrene (or, less likely, the 12-isomer), 11,12-dihydro-11, 12-dihydroxy-3-methylcholanthrene and the glutathione conjugate described above. Products with the properties of these compounds were formed when the epoxide was allowed to react with glutathione in an aqueous medium. Mouse-liver homogenate converted 3-methylcholanthrene into products with the chromatographic properties of 1- and 2-hydroxy-3-methylcholanthrene, cis- and trans-1, 2-dihydroxy-3-methylcholanthrene, 11,12-dihydro-11, 12-dihydroxy-3-methylcholanthrene, 3-methylcholanthrene-1- and -2-one and -1,2-quinone and the unidentified hydroxy-3-methylcholanthrenes. The syntheses of cis- and trans-1, 2-dihydroxy-3-methylcholanthrene, 3-methylcholanthrene-2-one, 2-hydroxy-3-methylcholanthrene, 3-methylcholanthrylene, 11,12-epoxy-11, 12-dihydro-3-methylcholanthrene and trans-11,12-dihydro-ll, 12-dihydroxy-3-methylcholanthrene are described.