ETHYLBENZENE MODULATES THE EXPRESSION OF DIFFERENT CYTOCHROME-P-450 ISOZYMES BY DISCRETE MULTISTEP PROCESSES

Ethylbenzene (EB) treatment to male Holtzman rats was shown to alter t he expression of cytochrome P-450s 1A1, 2B, 2C11, 2E1, and 3A, with se veral isozymes exhibiting complex multiphasic induction patterns when treated for 1 and 3 days with the alkylbenzene. Male rats were treated with daily i.p. injections of EB for either one or three days, and th e effects on P450 dependent activities, P450 immunoreactive protein le vels and their corresponding mRNA levels were measured. Although level s of P-450 2B, 2C11, 2E1, and 3A were all modulated by EB treatment, e ach exhibited different temporal characteristics. P-450 2B1/2B2 were i nduced after a single EB exposure and continued to be elevated after E B treatment for 3 days. However, P-450 2B1 and 2B2 mRNA levels were el evated about 50-fold after a single injection, and returned to control values after continued EB administration. P-450 2C11 expression was d ecreased to about 45% of controls after either single or repeated EB e xposure with corresponding changes being observed in the levels of 2C1 1 mRNA. P-450 2E1 was induced by EB according to a complex multistep i nduction pattern. Both P-450 2E1 protein and RNA levels were increased 2-4-fold after a single EB treatment but returned to control values a fter continued administration. P-450 3A-dependent testosterone 2 beta- hydroxylation and P-450 3A immunoreactive protein levels were both inc reased about S-fold after a single EB treatment, whereas levels were o nly elevated 2-fold after EB treatment for 3 days. In contrast, P-450 3A2 mRNA was unaffected by a single EB injection but was increased 3.5 -fold with repeated administration. Changes in P-450 3A1/2 were simila r to those observed with P-450 3A2, whereas changes in P-450 3A1/23 an d 3A23 mRNAs were not detectable. These data indicate that while EB ca n influence the expression of several P450 isozymes, the hydrocarbon a ppears to alter P-450 expression by acting at different regulatory ste ps.