Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines

Nanji, Amin A., Kalle Jokelainen, Maryam Fotouhinia, Amir Rahemtulla, Peter Thomas, George L. Tipoe, Grace L. Su, and Andrew J. Dannenberg. Increased severity of alcoholic liver injury in female rats: role of oxidatire stress, endotoxin, and chemokines. Am J Physiol Gastrointest Liver Physiol 281: G1348-G1356, 2002.--Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-KB (NF-[kappa]B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-[alpha] (TNF-[alpha]), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-[kappa]B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-[alpha] and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-[kappa]B activation and chemokine production, enhancing liver injury. TNF-[alpha] and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences. cytokines; cyclooxygenase-2; tumor necrosis factor-[alpha]