Vol. 302, Issue 2, 442-450, August 2002

Effect of Hyperinsulinemia and Type 2 Diabetes-Like Hyperglycemia on Expression of Hepatic Cytochrome P450 and Glutathione S-Transferase Isoforms in a New Zealand Obese-Derived Mouse Backcross Population

Georgia J. Pass¹, Walter Becker, Reinhart Kluge², Katharina Linnartz, Leona Plum, Kirsten Giesen and Hans-Georg Joost³

Institute for Pharmacology and Toxicology, Medical Faculty of the Technical University of Aachen, Aachen, Germany

In subgroups of a New Zealand obese mouse-derived backcross population with defined aberrations of glucose homeostasis, a comprehensive study of the hepatic expression of cytochrome P450 and glutathione S-transferase was performed. Three patterns of alterations in response to insulin resistance (normoglycemia/hyperinsulinemia) or diabetes (hyperglycemia/hypoinsulinemia) were observed: mRNA levels of Cyp2b9, Cyp3a16, Cyp4a14, and Gstt2 as assessed by Northern- and dot-blot analysis were increased markedly in liver from diabetic mice with no or only a slight increase in insulin resistant mice. Western-blot analysis detected the corresponding changes of the CYP2B and CYP4A proteins. In contrast, expression of Cyp2c22, Cyp2c29, and Cyp2c40 was reduced in diabetic, but normal in insulin resistant mice. These alterations were correlated with changes in serum free fatty acid levels and, therefore, seem to be mediated by the peroxisome proliferator activated receptor-. Furthermore, expression of Cyp1a2, Cyp7b1, Gstm3, and Gstm6 was reduced in both diabetic and insulin resistant mice. Because this third pattern was not correlated with the alterations of serum free fatty acid levels, it seems to reflect an early alteration in the course of the disease, and may be related to the progression of the syndrome from insulin resistance to the type 2-like diabetes.