Comparative effects of diabetogenic agents on hepatic drug metabolism
Chawalit, K.; Sretarugsa, P.; Thithapandha, A.
Drug Metabolism and Disposition the Biological Fate of Chemicals 10(1): 81-86
1982
ISSN/ISBN: 0090-9556 PMID: 6124390 Document Number: 190142
Chemical diabetes produced in male rats by treatment with alloxan (120 mg/kg, s.c.), 6-aminonicotinamide (35 mg/kg, i.p.), streptozotocin (55 mg/kg, i.p.) and N-methylacetamide (6.25 ml/kg, per os) prolonged hexobarbital sleeping time without affecting the awakening brain barbiturate level. Pharmacokinetic studies of aminopyrine in these diabetic animals also showed an increase in plasma half-life of the drug without any change in its volume of distribution. Aminopyrine N-demethylase activity from these rats was depressed although hepatic microsomal protein and cytochrome P-450 content were unaffected. Not all of these 4 agents decreased the metabolism of aniline. Aniline hydroxylase activity was increased by .apprx. 50% in animals treated with this dosage schedule of alloxan. Insulin (20 units/kg, once daily for 2 days) could antagonize the chemically induced changes in liver and body weight, blood glucose and activities of these drug-metabolizing enzymes. Glucose, insulin and all 4 diabetogens had no direct effect on the drug-metabolizing enzymes in vitro. This change (increase or decrease) in hepatic drug metabolism in these diabetic animals was found concurrently with a depletion of hepatic glycogen and a reduction in the circulating level of testosterone; hepatic glycogen content was reduced to approximately 30-50% of control; plasma testosterone concentration was reduced by about 1/2. The reduction in testosterone level was not likely to be the cause for the decrease in hepatic drug metabolism, inasmuch as testosterone administration (12 mg/kg, s.c., once daily for 2 days) could not restore the normal aminopyrine N-demethylase activity. Combination studies with microsomes and supernatant fractions from control and treated animals were consistent with the view that the locus of the effects of these diabetogens on hepatic drug metabolism is not cytosolic but is associated with a qualitative or quantitative change of the enzyme in the microsomal fraction itself. Sodium dodecyl sulfate/polyacrylamide gel-electrophoresis protein profiles exhibited by diabetic microsomes were apparently different from that shown by normal microsomes.