Selective induction of rat liver microsomal cytochrome P-448 by 3,4,5,3',4'-pentachlorobiphenyl and its effect on liver microsomal drug metabolism.

Abstract

Pretreatment of rats with 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB) at a single i.p. dose of 10 mg/kg caused a marked increase of cytochrome P-448 (P448) in liver microsomes. The liver microsomes of PenCB-treated rats (PenCB-microsomes) showed similar but somewhat different properties from those of 3-methylcholanthrene (MC)-treated rats (MC-microsomes) with respect to its CO difference spectrum, electrophoretic pattern on sodium dodecyl sulfate (SDS)-polyacrylamide gel and immunochemical reactivity with the antibodies prepared against the hemoproteins from phenobarbital (PB)- or β-naphthoflavone (BNF)-treated rat liver microsomes. Furthermore, PenCB pretreatment decreased not only demethylation of aminopyrine and codeine, but also hydroxylation of aniline, to which PenCB-microsomes showed lower affinity than MC-microsomes. Trace amounts of PenCB inhibited the metabolism of aniline and aminopyrine by MC-microsomes but not by untreated rat liver microsomes. On SDS-polyacrylamide gel electrophoretograms the ratio of cytochrome P450 (P450) to P448 in PenCB-microsomes was much smaller than that in MC-microsomes. These results may suggest that a part of the differences between the catalytic properties of PenCB- and MC-microsomes is due to the inhibitory effect of residual PenCB in PenCB-microsomes or/and the marked change of a relative ratio of P450 to P448 in PenCB-microsomes. A possibility that PenCB may induce a different P448 from that induced by MC is also discussed.