Suppressed expression of phenobarbital-inducible hepatic cytochrome P-450s in Eisai-hyperbilirubinuria rats (EHBR/Eis).
The differential induction of hepatic cytochrome P-450 (P450) was studied in Eisai-hyperbilirubinuria rats (EHBR/Eis). This rat is a mutant that has as high a concentration of bilirubin in the urine as in the plasma. A single administration of trans-stilbene oxide (TSO, 2 mmol/kg), a phenobarbital (PB)-type P450 inducer, did not increase total P450, the CYP2B1/2 or the CYP2C6 in EHBR/Eis liver. TSO was able to induce delta-aminolevulinic acid synthetase and heme oxygenase, rate-limiting enzymes in heme biosynthesis and degradation, respectively, in both EHBR/Eis and Sprague-Dawley rat (SDR), the strain from which EHBR/Eis is derived. TSO also produced similar effects on glutathione depletion and on the activities of other drug-metabolizing enzymes in both strains. A 23-fold increase in CYP2B1/2 mRNA in the SDR liver was observed 24 hr after TSO treatment. In the EHBR/Eis strain, however, TSO increased CYP2B1/2 mRNA only 2-fold. In addition, repeated injection of TSO failed to induce P450 isozymes, CYP2B1/2, CYP2C6 or CYP3A2 in EHBR/Eis. On the other hand, there was essentially no difference in the induced levels of CYP1A1/2 apoprotein and mRNA between twins of SDR and EHBR/Eis livers treated with 3-methylcholanthrene or 1-benzylimidazole. The increased levels of both CYP2B1/2 apoprotein and mRNA from EHBR/Eis liver treated with TSO and 1-benzylimidazole were much smaller (2.5- and 5-fold increases, respectively) than from the SDR liver (17.5- and 15-fold increases, respectively). Although PB expressed CYP2B1/2 apoprotein and mRNA to a similar extent in both homozygous and heterozygous EHBR/Eis livers, CYP3A2 and CYP2C6 were less responsive to PB in homozygous EHBR/Eis. Repeated treatment with TSO induced these isozymes in heterozygote but not in homozygote. These findings suggest that the suppressed expression of PB-inducible P450 isozyme genes in the EHBR/Eis liver may be a general phenomenon associated with PB-type inducers. Therefore, EHBR/Eis may be experimentally useful for studying the mechanism of P450 induction by PB and PB-type inducers.
Oguro
T
T
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Kaneko
E
E
Kaneko
Y
Y
Numazawa
S
S
Imaoka
S
S
Funae
Y
Y
Mikami
T
T
Yoshida
T
T
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D006932:Hyperbilirubinemia / Q000378:metabolism*; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects*; D008297:Male; D008861:Microsomes / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors
D013267:Stilbenes; D003577:Cytochrome P-450 Enzyme System; C025906:stilbene oxide; D010634:Phenobarbital