2,4,5,2',4',5'-hexachlorobiphenyl (
HCB) induces hepatic microsomal
cytochromes P450 with a similar selectivity for responsive genes to
phenobarbital (PB). CYP2Bl,
CYP2B2, CYP2C6, CYP3Al, and CYP2Al each showed large strain differences in induction by
HCB Fisher F344 >> Wistar Furth (WF) that were much more evident in female rats, paralleling previous observations with PB. These five P450s and
epoxide hydrolase were, however, induced more effectively by
HCB than by PB and strain differences were even larger. With
HCB, strain differences in male rats were much more apparent than with PB. This change was not due to the greater
HCB induction since a 2-fold lower induction was maintained even with a 10-fold lower dose of
HCB. The sex and strain differences were seen both by immunoblot analysis and by form-selective
enzyme activity assays. induction of
CYP2B1,
CYP2B2, and CYP3A1 by
HCB was decreased 3-fold when
starvation during the final 24 hr was replaced by continuous feeding. This effect was similar in each strain and therefore independent of the regulatory processes associated with the differential suppression of induction in WF rats. This modulation of induction by feeding was also seen with PB which caused only a 30% lowering of induction in continuously fed F344 rats. A 52-kDa microsomal
protein (p52) was prominently induced by both
HCB and PB after
starvation, while minor induction of a 50-kDa microsomal
protein (p50) also occurred after the same treatment. Furthermore, a 100-kDa microsomal
protein (p100) was induced by
HCB but not by PB and only in rats that were continuously fed. These results suggest that the induction of multiple forms of P450 following
HCB treatment functions through the same PB-stimulated pathway that shows a strain-dependent endocrine (GH/T3/
testosterone)-sensitive suppression mechanism. The induction of p5O, p52, and plOO by
HCB suggests the presence of at least two additional hepatic response mechanisms for
HCB.