Differential induction of cytochromes P450 and cytochrome P450-dependent arachidonic acid metabolism by 3,4,5,3',4'-pentachlorobiphenyl in the rat and the guinea pig.

Differential induction of hepatic cytochromes P450 by 3,4,5,3',4'-pentachlorobiphenyl (PENCB) has been observed in the rat and the guinea pig: (1) in rat and guinea pig, treatment with the chosen dose levels resulted in significant induction of total, carbon monoxide-discernible cytochrome P450 content; the absorption maximum of the CO-adduct of the dithionite-reduced microsomes from PENCB-induced rat liver was shifted from 450 to 448 nm, whereas its counterpart in the guinea pig did not; (2) PENCB treatment significantly increased EROD activity in rat liver microsomes (up to 60-fold), but the increase in the guinea pig was less than fivefold; (3) PENCB-induced rat liver microsomes significantly induced the omega-1 hydroxylation of arachidonic acid (AA); however, omega-1 hydroxylation of AA was hardly affected by PENCB treatment in the guinea pig. Instead, omega-hydroxylation was significantly increased in this latter species. In addition to omega-1 hydroxylation in the rat or omega-hydroxylation in the guinea pig, an additional AA metabolite (designated peak III) was significantly induced by PENCB in both rat and guinea pig; (4) Western blot and ELISA analyses with polyclonal anti-P450 IA1/IA2 and IVA1 antibodies demonstrated that P450 IA1 was significantly induced in the rat but only slightly induced in the guinea pig, whereas P450 IVA1 was significantly suppressed in the rat but significantly induced in the guinea pig by PENCB treatment. The induction of the third arachidonic acid metabolite peak, Peak III, in both rat and guinea pig, particularly in the guinea pig, is obviously neither mediated by P450 IA1 nor by P450 IV A1. At present, it is still unclear which form(s) of cytochrome P450 isoenzymes is responsible for this latter hydroxylation of arachidonic acid.