Modulation of xenobiotic metabolism and oxidative stress in chronic streptozotocin-induced diabetic rats fed with Momordica charantia fruit extract

Abstract

ABSTRACT:We studied the long-term effects of streptozotocin-induced diabetes on tissue-specific cytochrome P450 (CYP) and glutathione-dependent (GSHdependent) xenobiotic metabolism in rats. In addition, we also studied the effect of antidiabetic Momordica charantia (karela) fruit-extract feeding on the modulation of xenobiotic metabolism and oxidative stress in rats with diabetes. Our results have indicated an increase (35-50%) in CYP4A-dependent lauric acid hydroxylation in liver, kidney, and brain of diabetic rats. About a two-fold increase in CYP2E-dependent hepatic aniline hydroxylation and a 90-100% increase in CYP1A-dependent ethoxycoumarin-O-deethylase activities in kidney and brain were also observed. A significant increase (80%) in aminopyrene N-demethylase activity was observed only in rat kidney, and a decrease was observed in the liver and brain of diabetic rats. A significant increase (77%) in NADPH-dependent lipid peroxidation (LPO) in kidney of diabetic rats was also observed. On the other hand, a decrease in hepatic LPO was seen during chronic diabetes. During diabetes an increased expression of CYP1A1, CYP2E1, and CYP4A1 isoenzymes was also seen by Western blot analysis. Karela-juice feeding modulates the enzyme expression and catalytic activities in a tissue-and isoenzyme-specific manner. A marked decrease (65%) in hepatic GSH content and glutathione S-transferase (GST) activity and an increase (about two-fold) in brain GSH and GST activity was observed in diabetic rats. On the other hand, renal GST was markedly reduced, and GSH content was moderately higher than that of control rats. Western blot analyses using specific antibodies have confirmed the tissue- specific alterations in the expression of GST isoenzymes. Karela-juice feeding, in general, reversed the effect of chronic diabetes on the modulation of both P450-dependent monooxygenase activities and GSHdependent oxidative stress related LPO and GST activities. These results have suggested that the modulation of xenobiotic metabolism and oxidative stress in various tissues may be related to altered metabolism of endogenous substrates and hormonal status during diabetes. The findings may have significant implications in elucidating the therapeutic use of antidiabetic drugs and management of Type 1 diabetes in chronic diabetic patients.

Regulation of Glutathione S-Transferase Mu with type 1 diabetes and its regulation with antioxidants

“…Conjugating the glutathione to a wide range of electrophiles, Glutathione S-transferases also reveal diverse response to lots of chemicals and oxidative stress in the normal and disease conditions as diabetes mellitus [32]. Our data also demonstrated that, excessive oxidative stress occurred in the liver due to diabetes mellitus, resulted in the down regulation of the expression GST-Mu gene.…”

Toxicological studies of Momordica charantia Linn Seed extracts in Male Mice

“…At maturity, the fruit splits into three irregular valves that curl backwards and release numerous reddish-brown seeds. Biological actions of various extracts of the plants or its constituents include antidiabetic (Ahmed et al, 1998;Mastuda et al, 1999;Raza et al, 2000), anti ulcerogenic (Gürbüz et al, 2000), antimutagenic (Guevara et al, 1990), antioxidant (Scartezzini & Speroni, 2000), anti-tumour (Lee-Huang et al, 1995a), immunomodulatory (Spreafico et al, 1983). Two proteins known as α -and β -monorcharin which are present in the seeds, fruits and leaves have shown to inhibit the human immune deficiency virus (HIV) in vitro (Zhang, 1992;LeeHuang et al, 1995b).…”

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

“…9 Overexpression of CYP2E1 is of direct importance to human health and is associated with a range of diseases, including diabetes mellitus, alcoholic liver disease, and cancer. [10][11][12] The expression level of CYP2E1 increases significantly in heart tissues in humans under ischemia; mice, rats, and dogs with dilated cardiomyopathy (DCM); and spontaneously hypertensive rats. [13][14][15][16][17][18] The overexpression of CYP2E1 is associated with several cellular markers of oxidative stress, as well as with decreased viability as a result of both necrosis and apoptosis.…”