ABSTRACT
Three major flavonoid chamomile components (quercetin, apigenin-7-O-glucoside and rutin) were subjected to oxidative metabolism by cytochrome P-450 of rat liver microsomal preparations. Changes over time in their respective concentrations were followed using reversed-phase HPLC with UV detection. No clean-up had to be applied as only the specific flavonoid had to be separated from the background components originating from the rat liver microsome.Neither the concentration of apigenin-7-O-glucoside nor that of the diglycoside rutin decreased during one hour of exposure to rat microsomal treatment. In contrast, the concentration of quercetin, a lipophilic aglycon, decreased.Our analytical HPLC results complement the in silico calculated lipophilicity (logP) of these compounds; the relatively high lipophilicity of quercetin appears to predispose it to oxidative metabolism in order to decrease its fat solubility. In contrast the much less lipophilic compounds apigenin-7-O-glucoside and rutin were resistant in vitro to microsomal treatment.
ABSTRACT
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.
