Treatment with omega-3 PUFAs does not increase the risk of CYP2E1-dependent oxidative stress and diabetic liver pathology

Abstract

An increase in CYP2E1 expression is a key factor in the development of diabetic oxidative liver damage. Long-term treatment with omega-3 PUFAs, which are CYP2E1 substrates, may affect CYP2E1 expression in the liver. In this work, we performed Western blot analysis, biochemical methods, and microscopic ultrastructural studies of the liver in a streptozotocin-induced rat model of type 1 diabetes to investigate whether long-term treatment with omega-3 PUFAs could induce CYP2E1-dependent oxidative stress and diabetic liver pathology. Significant hyperglycemia and lack of natural weight gain were observed in the diabetic rats compared to non-diabetic controls. A 2.5-fold increase in CYP2E1 expression (protein content and activity) was also observed in the diabetic rats. In addition, signs of oxidative stress were found in the liver of the diabetic rats. A significant increase in transaminases and GGT level in blood serum was also observed, which could indicate marked destruction of liver tissue. Diabetic dyslipidemia (increased triacylglycerol levels and decreased HDL-C levels) was found. Treatment of the diabetic animals with an omega-3-enriched pharmaceutical composition of PUFAs had no effect on CYP2E1 levels but contributed to a two-fold decrease in enzyme activity. The intensity of lipid peroxidation also remained close to the diabetic group. However, at the same time, antioxidant protection was provided by induction of antioxidant enzyme activity. Examination of the liver ultrastructure revealed no characteristic signs of diabetic pathology. However, omega-3 PUFAs did not normalize blood glucose levels and serum lipid profile. Thus, long-term treatment of diabetic rats with omega-3 PUFAs does not increase the risk of CYP2E1-dependent oxidative stress and development of liver pathology but prevents some diabetic ultrastructural damage to hepatocytes.

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

“…The exact reasons for these discrepancies are unknown although higher APAP glucuronidation and improved liver repair in diabetic animals might play a role [ 189 – 191 ]. However, it is worth mentioning that hepatic CYP2E1 activity was not increased in these studies, thus contrasting with many other investigations reporting CYP2E1 induction in streptozotocin-treated rodents [ 10 , 167 , 185 – 188 ]. Further studies would be needed in order to determine why hepatic CYP2E1 induction is not always observed in streptozotocin-induced experimental diabetes.…”

“…Another study in rats fed a diet with 20% fish oil (i.e., rich in n-3 PUFAs) also reported protection against APAP-induced acute liver injury, which was deemed to be related to higher APAP glucuronidation [ 166 ]. Interestingly, n-3 PUFAs reduced hepatic CYP2E1 activity in insulinopenic diabetic rats [ 167 ] but their protective effect against APAP hepatotoxicity was not investigated in this study.…”

“…Although not investigated in this study, it is possible that CYP2E1 induction might also have played a role in liver injury aggravation [ 10 ]. Indeed, numerous studies (but not all—see below) showed that streptozotocin-induced diabetes is associated with higher hepatic CYP2E1 protein expression and activity [ 10 , 167 , 185 – 188 ].…”

Alleviation of D-gal-induced senile liver injury by Rg3, a signature component of red ginseng

“…Among other things, ROS are transmitted to mitochondria via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system as well as the respiratory chain [9,10]. Apart from mitochondria, overexpression of cytochrome P450 2E1 (CYP2E1) and 4-Hydroxynonenal (4-HNE) further damage hepatocytes [11].…”