Abstract
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 glutathioneS-transferase was performed. Three patterns of alterations in response to insulin resistance (normoglycemia/hyperinsulinemia) or diabetes (hyperglycemia/hypoinsulinemia) were observed: mRNA levels ofCyp2b9, 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-α. 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.
Footnotes
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↵1 Current address: Merck, Sharp and Dohme, Terlings Park, Harlow, Essex, UK.
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↵2 Current address: Institute of Laboratory Animal Research, Medical Faculty of the Technical University of Aachen, Aachen, Germany.
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↵3 Current address: German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
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This project was supported by the Deutsche Forschungsgemeinschaft Grant FOR 441, Jo117/11-2.
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DOI: 10.1124/jpet.102.033553
- Abbreviations:
- NZO
- New Zealand obese
- NSZO
- NZO × F1 (SJL × NZO) backcross population
- P450
- cytochrome P450
- FFA
- free fatty acids
- GST
- glutathione S-transferase
- PPAR
- peroxisome proliferator activated receptor
- BG
- blood glucose
- PI
- plasma insulin
- SSC
- standard saline citrate
- EST
- expressed sequence tags
- SJL
- Swiss Jackson Laboratory
- Received January 22, 2002.
- Accepted April 5, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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