RELATIONSHIP BETWEEN HYDROCARBON STRUCTURE AND INDUCTION OF P450 - EFFECTS ON PROTEIN-LEVELS AND ENZYME-ACTIVITIES

1. Treatment of male rat with the small aromatic hydrocarbons, benzene , toluene, ethylbenzene, n-propylbenzene, m-xylene, and p-xylene incre ased several P450-dependent activities, with ethylbenzene, m-xylene, a nd n-propylbenzene producing the greatest response. Hydrocarbon treatm ent differentially affected toluene metabolism, producing a response d ependent on the metabolite monitored. In untreated rats, benzyl alcoho l was the major hydroxylation product of toluene metabolism, comprisin g > 99% of the total metabolites formed. Hydrocarbon treatment increas ed the overall rate of toluene metabolism by dramatically increasing t he amount of aromatic hydroxylation. Ethylbenzene, n-propylbenzene and m-xylene were the most effective inducers of aromatic hydroxylation o f toluene. In contrast, production of the major toluene metabolite ben zyl alcohol was increased only after treatment with m-xylene. 2. P450 2B1/2B2 levels were induced by each of the hydrocarbons examined, with the magnitude of induction increasing with increasing hydrocarbon siz e. P450 1A1 was also induced after hydrocarbon exposure; however, the degree of induction was smaller than that observed for P450 2B1/2B2. P 450 2C11 levels were suppressed after treatment with benzene, ethylben zene and n-propylbenzene. 3. Taken together these results display two induction patterns. The first generally corresponds to changes in the P450 2B subfamily, where activities (e.g. the aromatic hydroxylations of toluene) were most effectively induced by ethylbenzene, n-propylben zene and m-xylene. In the second, induction was observed only after m- xylene treatment, a pattern that was found when the metabolism of the substrate was catalysed by both the P450 2B subfamily and P450 2C11. H ydrocarbons that both induced P450 2B1/2B2 and suppressed P450 2C11 (s uch as ethylbenzene and n-propylbenzene) showed little change in activ ities catalysed by both isozymes (e.g. aliphatic hydroxylation of tolu ene, and aniline hydroxylation); however, m-xylene treatment led to el evated P450 2B1/2B2 levels without significantly suppressing P450 2C11 . m-Xylene produced significant increases in activities efficiently ca talysed by both isozymes. Therefore, the unique induction pattern obse rved after m-xylene treatment can be accounted for by induction of P45 0 2B1/2B2 without concomitant suppression of P450 2C11.