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 increased several P450-dependent activities, with ethylbenzene, m-xylene, and n-propylbenzene producing the greatest response. Hydrocarbon treatment differentially affected toluene metabolism, producing a response dependent on the metabolite monitored. In untreated rats, benzyl alcohol was the major hydroxylation product of toluene metabolism, comprising > 99% of the total metabolites formed. Hydrocarbon treatment increased the overall rate of toluene metabolism by dramatically increasing the amount of aromatic hydroxylation. Ethylbenzene, n-propylbenzene and m-xylene were the most effective inducers of aromatic hydroxylation of toluene. In contrast, production of the major toluene metabolite benzyl 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 size. P450 1A1 was also induced after hydrocarbon exposure; however, the degree of induction was smaller than that observed for P450 2B1/2B2. P450 2C11 levels were suppressed after treatment with benzene, ethylbenzene 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-propylbenzene 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. Hydrocarbons that both induced P450 2B1/2B2 and suppressed P450 2C11 (such as ethylbenzene and n-propylbenzene) showed little change in activities catalysed by both isozymes (e.g. aliphatic hydroxylation of toluene, and aniline hydroxylation); however, m-xylene treatment led to elevated P450 2B1/2B2 levels without significantly suppressing P450 2C11. m-Xylene produced significant increases in activities efficiently catalysed by both isozymes. Therefore, the unique induction pattern observed after m-xylene treatment can be accounted for by induction of P450 2B1/2B2 without concomitant suppression of P450 2C11.
Backes
W L
WL
Department of Pharmacology, Louisiana State University Medical Center, New Orleans 70112.
Sequeira
D J
DJ
Cawley
G F
GF
Eyer
C S
CS
D000818:Animals; D001554:Benzene / Q000633:toxicity; D001555:Benzene Derivatives / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000145:classification; D004790:Enzyme Induction / Q000187:drug effects; D006838:Hydrocarbons / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014050:Toluene / Q000378:metabolism / Q000633:toxicity; D014992:Xylenes / Q000633:toxicity
D001555:Benzene Derivatives; D006838:Hydrocarbons; D014992:Xylenes; C024268:n-propylbenzene; D014050:Toluene; C031286:4-xylene; D003577:Cytochrome P-450 Enzyme System; D001554:Benzene; C004912:ethylbenzene; C031285:3-xylene