A. Irizar et al., DEFECTIVE EXPRESSION OF CYTOCHROME-P450 PROTEINS IN THE LIVER OF THE GENETICALLY-OBESE ZUCKER RAT, European journal of pharmacology. Environmental toxicology and pharmacology section, 293(4), 1995, pp. 385-393
The hepatic expression of xenobiotic-metabolising cytochrome P450 isof
orms in the genetically obese Zucker rat, a model of obesity, was comp
ared to that of its lean littermate. Cytochrome P450 (CYP) levels were
determined using diagnostic substrates and/or immunologically in West
ern blot analyses. When compared with the lean Zucker rat, the obese a
nimal exhibited hyperglycaemia, hypercholesterolaemia, marked hyperins
ulinaemia and hypertriglyceridaemia but was normoketonaemic. CYP3A and
CYP1A2 levels were higher in the obese Zucker rat when compared with
the lean littermate but, in contrast, a protein recognised by human CY
P2D6 and, to a lesser extent, CYP2C11 levels were lower. Pretreatment
with acetone, dexamethasone and clofibrate resulted in enhanced p-nitr
ophenol hydroxylase (CYP2E), erythromycin N-demethylase (CYP3A) and la
uric acid hydroxylase (CYP4A) activities respectively in the liver of
the lean Zucker rat but, in contrast, the obese Zucker rat was refract
ive to such treatment; similarly, hepatic apoprotein levels of the CYP
2E and CYP4A subfamilies were increased markedly only in the lean Zuck
er rat. It is concluded that CYP2E, CYP3A and CYP4A subfamilies are po
orly expressed in the obese Zucker rat, and this rat strain may serve
as a good model for elucidating the molecular mechanisms of induction
of these cytochrome P450 proteins.