Reduced hepatic expression of CYP7A1 and CYP2C13 in rats with spontaneous hyperlipidaemia.
A strain of hyperlipidaemic Sprague-Dawley (HSD) rat was compared with normal Sprague-Dawley (SD) rats for expression of cholesterol 7alpha-hydroxylase activity (CYP7A1) and other cytochrome P450 (P450) enzymes in liver. Hepatic microsomal CYP7A1 activity in male HSD rats was 2-3-fold lower than in male SD rats with CYP7A1 apoprotein levels being similarly reduced. CYP7A1 expression was subject to diurnal variation in HSD rats as found in SD rats. Treatment of HSD rats with cholestyramine caused an increase in hepatic microsomal cholesterol 7alpha-hydroxylase activity of 3.3-fold compared with a 3.5-fold increase in SD rats with similar changes in apoprotein levels. These results indicate that the lower activity in HSD rats is not due to a defect in the catalytic activity of the enzyme, regulation affecting diurnal variation or regulation through bile acid feedback inhibition. No difference between hepatic microsomal methoxyresorufin-O-demethylase, benzoxyresorufin-O-debenzylase or chlorzoxazone 6-hydroxylase activities in SD and HSD rats was found, nor was there any difference in the levels of CYP1A2, CYP2D1, CYP2E1, CYP3A1, CYP3A2 or NADPH cytochrome P450 reductase determined by immunoblotting using specific anti-peptide antibodies. However, unlike in male SD rats, CYP2C13 was absent in male HSD rats and this was associated with a two-fold reduction in testosterone 6beta-hydroxylase activity. In conclusion, while HSD rats do not have a general reduction in P450 levels, they do lack CYP2C13 and have lowered cholesterol 7alpha-hydroxylase activity, as a result of a reduced level of expression of the enzyme.
Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK. BRASSIL@servier.co.uk
P J
PJ
Brassil
K
K
Debri
H
H
Nakura
S
S
Kobayashi
D S
DS
Davies
R J
RJ
Edwards
D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006949:Hyperlipidemias / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; C113764:Cyp2c13 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase