Insulin in flavin-containing monooxygenase regulation. Flavin-containing monooxygenase and cytochrome P450 activities in experimental diabetes.
Microsomal monooxygenases - cytochrome P450 (CYP, EC 1.14.14.1) and flavin-containing monooxygenase (FMO, EC 1.14.13.8) - have profound roles in drug metabolism. While the induction of some metabolic enzymes such as hepatic FMO and intestinal CYP1A, CYP2B is recognized in experimental diabetes, the effect of insulin treatment on FMO and intestinal CYP3A in diabetic animals has not been reported before. Changes in abundance and activity of hepatic and intestinal microsomal CYPs and FMO were studied in streptozotocin-induced diabetic rats either treated or not with insulin. Hepatic FMO1 activity increased in diabetic rats, but it was restored to control value on insulin treatment. Insulin itself had no effect on FMO1 activity in non-diabetic animals. A remarkable increase of total CYP content was accompanied by a reduced CYP3A specific enzyme activity in the small intestine of diabetic animals. The extent of these changes decreased on insulin treatment. Both, hepatic FMO1 and intestinal CYP3A activity correlated with average blood glucose concentration in untreated diabetic rats. These results indicate that insulin is involved in the regulation of hepatic FMO1 and intestinal CYP3A in rats. Blood glucose level is a good marker for FMO induction. The marked reduction of intestinal CYP3A capacity suggests that diabetes exerts a substantial effect on the activity of most determining intestinal CYP enzyme.
Borbás
Tímea
T
Division of Pharmacology and Drug Safety, Richter Gedeon Ltd., Gyömroi út 19-21, 1475 Budapest, P.O. Box 27, Hungary.
Benko
Bernadett
B
Dalmadi
Balázs
B
Szabó
Imola
I
Tihanyi
Károly
K
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007004:Hypoglycemic Agents; D007328:Insulin; D007527:Isoenzymes; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D008995:Monoamine Oxidase