Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes.
Enhanced hepatic levels of cytochrome P450 2E1 (CYP2E1) may play a key role in the pathogenesis of some liver diseases because CYP2E1 represents a significant source of reactive oxygen species. Although a large fraction of CYP2E1 is located in the endoplasmic reticulum, CYP2E1 is also present in mitochondria. In this study, we asked whether ethanol, a known inducer of microsomal CYP2E1, could also increase CYP2E1 within mitochondria. Our findings indicated that ethanol increased microsomal and mitochondrial CYP2E1 in cultured rat hepatocytes and in the liver of lean mice. This was associated with decreased levels of glutathione, possibly reflecting increased oxidative stress. In contrast, in leptin-deficient obese mice, ethanol administration did not increase mitochondrial CYP2E1, nor it depleted mitochondrial glutathione, suggesting that leptin deficiency hampers mitochondrial targeting of CYP2E1. Thus, ethanol intoxication increases CYP2E1 not only in the endoplasmic reticulum but also in mitochondria, thus favouring oxidative stress in these compartments.
Robin
Marie-Anne
MA
INSERM Unité 481, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. robin@bichat.inserm.fr
Sauvage
Ingrid
I
Grandperret
Thomas
T
Descatoire
Véronique
V
Pessayre
Dominique
D
Fromenty
Bernard
B
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D000431:Ethanol / Q000633:toxicity*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000737:chemistry / Q000187:drug effects; D013997:Time Factors
D009243:NAD; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1