Ethylbenzene-mediated induction of cytochrome P450 isozymes in male and female rats.
Male and female Holtzman rats were exposed to ethylbenzene, and the effect on liver microsomal activities was studied. Hydrocarbon- and sex-dependent effects on P450-dependent metabolism of drugs and aromatic hydrocarbons were investigated. Hydrocarbon treatment produced two patterns of induction in cytochrome P450-dependent activities: (1) induction common to both sexes; and (2) induction exclusively in females. Benzphetamine N-demethylation, 7-ethoxycoumarin O-deethylation, p-nitroanisole O-demethylation and aromatic hydroxylation of toluene were induced in both sexes after rats were exposed to ethylbenzene. The rate of benzphetamine N-demethylation increased 4-fold in females and nearly doubled in males. The increase in O-deethylation of 7-ethoxycoumarin was 3-fold in females and doubled in males, while p-nitroanisole O-demethylation increased 4-fold in both sexes after exposure to ethylbenzene. Ethylbenzene had its greatest effect upon the formation of aromatic hydroxylated metabolites of toluene. Ethylbenzene exposure increased the rate of o-cresol formation by 4- and 9-fold in female and male rats, respectively. The formation rate of p-cresol was undetectable in either sex prior to hydrocarbon exposure; however, after the rats were given ethylbenzene, rates increased to 0.4 nmol/min/mg protein in females and to 0.9 nmol/min/mg protein in the males. Ethylbenzene exposure selectively induced aminopyrine demethylation, aniline hydroxylation, N,N-dimethylnitrosamine N-demethylation (DMNA) and aliphatic hydroxylation of toluene in females. Rates for aminopyrine, aniline, and DMNA were increased 50% over controls, while formation of benzyl alcohol from toluene was enhanced to 260% of control. Western immunoblotting indicated that ethylbenzene treatment induced cytochrome P450 2B1/2B2 to a greater extent in male rats and cytochrome P450 2E1 only in females. Ethylbenzene exposure did not affect significantly the level of cytochrome P450 1A1.
Sequeira
D J
DJ
Department of Pharmacology, Louisiana State University Medical Center, New Orleans 70112.
Eyer
C S
CS
Cawley
G F
GF
Nick
T G
TG
Backes
W L
WL
D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D019905:Benzyl Alcohol; D001592:Benzyl Alcohols / Q000378:metabolism; D015153:Blotting, Western; D003408:Cresols / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015786:Cytochromes b5 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000096:biosynthesis; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D051381:Rats; D012737:Sex Factors; D014050:Toluene / Q000378:metabolism
D001555:Benzene Derivatives; D001592:Benzyl Alcohols; D003408:Cresols; C032538:4-cresol; D014050:Toluene; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D009245:NADH Dehydrogenase; C004912:ethylbenzene; D019905:Benzyl Alcohol; C034047:2-cresol