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Effect of genetic obesity and experimental diabetes on hepatic microsomal mixed function oxidase activities
Author(s) -
ZALUZNY LOUISE,
FARRELL GEOFFREY C.,
MURRAY MICHAEL
Publication year - 1990
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.1990.tb01626.x
Subject(s) - medicine , endocrinology , androstenedione , microsome , insulin , microsoma , diabetes mellitus , streptozotocin , cytochrome p450 , chemistry , enzyme , metabolism , biochemistry , hormone , androgen
Abstract In male rats, genetic obesity and experimental diabetes are associated with altered activities of several of the hepatic microsomal P‐450 isozymes concerned with steroid and xenobiotic oxidation. The present study examined the roles of insulin and ketonaemia in effecting these changes. In obese male Zucker rats, androstenedione 6β‐, 16α‐ and 16β‐hydroxylase activities (mediated by P450 PCN‐E , P‐450 UT‐A and P450 PB‐B , respectively) were significantly decreased to 21%, 20% and 43% of lean control. Obesity was also associated with a significant decrease in the activities of N ‐nitrosodimethylamine demethylase (P‐450j) and aniline p ‐hydroxylase to about 70%. A similar decrease in total microsomal P‐450 was also observed. Androstenedione 7α‐hydroxylase activity (mediated by P‐450 UT‐F ) was unchanged in these animals. In streptozotocin‐induced diabetic male Wistar rats, androstenedione 7α‐ and 16β‐hydroxylase activities were significantly elevated to 230% and 270% of control, respectively. Significant increases in the rates of N ‐nitrosodimethylamine demethylase and aniline p ‐hydroxylase were also noted in diabetic rat liver. In contrast, the activity of P‐450 UT‐A was reduced to 30% of control and P‐450 PCN‐E ‐specific 6β‐hydroxylation was unchanged. Control of the diabetic state with insulin treatment reversed all the changes in P‐450‐mediated activities. Significant correlations were found between serum concentrations of insulin and catalytic activities of P‐450 PB‐B , (ρ= ‐0.46), P‐450 UT‐F (ρ= ‐0.65) and P‐450j (ρ= ‐0.71). Positive correlations of the same magnitude were also found between these mixed function oxidase activities and β‐hydroxybutyrate. These studies provide further evidence that hormones and ketone bodies are involved, either directly or indirectly, in the alteration of hepatic P‐450‐mediated metabolism of sex steroids and foreign compounds. In particular, insulin appears to exert a negative control on P‐450j and P‐450 PB‐B activities.