Studies in detoxication. 69. The metabolism of alkylbenzenes: n-propylbenzene and n-butylbenzene with further observations on ethylbenzene

TLDR: Observations on the metabolism of ethylbenzene have now shown that this compound undergoes co-oxidation, although the major process is a-Oxidation.

Abstract: An account of our studies on the metabolic fate of toluene, ethyl-, i8opropyland tert.-butyl-benzenes has been given in earlier papers (Smith, Smithies & Williams, 1954a, b, c; Robinson, Smith & Williams, 1955; Robinson & Williams, 1955). The present paper deals with n-propyland n-butyl-benzenes. These two compounds were previously studied by Thierfelder & Klenk (1924), who showed that npropylbenzene was oxidized in rabbits to yield benzoic acid (excreted as hippuric acid) and nbutylbenzene to yield phenylacetic acid (excreted as phenaceturic acid). It was suggested that about 60-65% of these compounds were oxidized to acids and it was concluded that these alkylbenzenes underwent co-oxidation initially and then, by ,Boxidation of the resulting w-carboxylic acid, they were converted into benzoic or phenylacetic acid according to the number of carbon atoms in the alkyl side chain. However, Smith et al. (1954a) found that n-propyland n-butyl-benzenes gave rise to appreciable amounts of non-reducing conjugated glucuronic acids, and suggested that the alkyl side chains of these compounds were oxidized in other positions as well as the wto yield secondary alcohols which were excreted conjugated with glucuronic acid. Both propyland butylbenzene could be expected to be oxidized at the a-position, since this is activated by its proximity to the benzene ring (cf. ethylbenzene, Smith et al. 1954b). Furthermore, it has been observed that alkyl side chains in barbiturates (Maynert, 1952) and the n-butyl chain in the antirheumatic drug, phenylbutazone (butazolidine) (Bums et al. 1955), are oxidized in the (co 1)-position. This type of oxidation could also occur with n-propyland nbutyl-benzene. It will, in fact, be shown here that both these compounds are oxidized in rabbits at the aand (w 1)-positions of the alkyl side chain. Further observations on the metabolism of ethylbenzene have now shown that this compound undergoes co-oxidation, although the major process is a-oxidation.