Dose-response relationships for cytochrome P450 induction by phenobarbitalin the cotton rat (Sigmodon hispidus)

The induction of a hepatic pleiotropic response, including increase in live r/body weight ratio, induction of hepatic CYP2B and CYP3A protein and catal ytic activity, and hepatic microsomal epoxide hydration activity, was inves tigated in male cotton rats (Sigmodon hispidus) administered graded dietary concentrations (0-1500 ppm) of phenobarbital (PB) for 14 days. A dose-depe ndent induction of each endpoint was observed, although plateaus in the var ious dose-response curves were not obtained, and ED50 values (PB concentrat ions associated with half-maximal responses) for the various endpoints were not able to be calculated. A maximal 1.31-fold increase, compared to the c ontrol value, in liver/body weight ratio was observed, while microsomal epo xide hydration activity was increased as much as 3.6-fold by PB administrat ion. Pentoxy- and benzyloxyresorufin O-dealkylation and testosterone 16 bet a-hydroxylation activities (considered to be relatively selective for CYP2B in the Norway rat (Rattus norvegicus)), were induced maximally less than f ive-fold. Testosterone 6 beta-hydroxylation (considered to be relatively se lective for CYP3A in R. norvegicus) was induced maximally less than two-fol d. Maximal induction of 7-ethoxy-4-trifluorometlhyl-coumarin O-deethylation was 18-fold, compared to the control rate. Western blotting studies indica ted that hepatic microsomal proteins immunoreactive with polyclonal antiser a to R. norvegicus CYP2B1 or CYP3A1 were induced, in a dose-responsive mann er, by PB in the cotton rats. These results indicate that the cotton rat re sponds to PB treatment with a coordinate pleiotropic response similar to th at displayed by R. norvegicus, although the substrate specificity of the in duced proteins appears to differ between the two rodent species. (C) 1998 P ublished by Elsevier Science Inc.