Hepatic cytochrome P-450j induction in the spontaneously diabetic BB rat.
Hepatic microsomal cytochrome P-450j has been studied using the male spontaneously diabetic BB rat as a model for insulin-dependent diabetes. This approach avoids any direct hepatotoxic effects from chemical diabetogenic agents. Both diabetic rats maintained on insulin and nondiabetic littermates were used as controls. Levels of cytochrome P-450j were increased approximately 3-fold in the diabetics 4 days after the cessation of insulin therapy. In addition, cytochrome P-450j-catalyzed enzymatic activities, aniline hydroxylation, and N-nitrosodimethylamine N-demethylation were increased by the diabetic state at this same time period. Cytochrome P-450f remained at control levels in all groups of animals. In order to test the hypothesis that ketone bodies are involved in the increase in cytochrome P-450j in the diabetic state, plasma beta-hydroxybutyrate levels were monitored. Hepatic aniline hydroxylation, N-nitrosodimethylamine N-demethylation, and cytochrome P-450j levels in individual animals were found to correlate with plasma beta-hydroxybutyrate levels (r = 0.59-0.71 p less than 0.001). In contrast, no significant correlation between levels of cytochrome P-450j and plasma glucose, insulin, or cholesterol was observed in individual animals (r = 0.07-0.23, p greater than 0.4). We conclude that cytochrome P-450j is induced in the livers of spontaneously diabetic rats, and that this induction may be associated directly or indirectly with elevated plasma ketone levels.
Bellward
G D
GD
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Chang
T
T
Rodrigues
B
B
McNeill
J H
JH
Maines
S
S
Ryan
D E
DE
Levin
W
W
Thomas
P E
PE
D020155:3-Hydroxybutyric Acid; D000815:Aniline Hydroxylase / Q000032:analysis; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004128:Dimethylnitrosamine / Q000378:metabolism; D004790:Enzyme Induction; D006885:Hydroxybutyrates / Q000097:blood; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats
D006885:Hydroxybutyrates; D007328:Insulin; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D004128:Dimethylnitrosamine; D020155:3-Hydroxybutyric Acid