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

Amin A. Nanji, Kalle Jokelainen, Maryam Fotouhinia, Amir Rahemtulla, Peter Thomas, George L. Tipoe, L. S U Grace, Andrew J. Dannenberg

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


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- KB) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-α (TNF-α), 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- KB activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-α 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- KB activation and chemokine production, enhancing liver injury. TNF-α and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.

Original languageEnglish (US)
Pages (from-to)G1348-G1356
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number6 44-6
StatePublished - 2001


  • Cyclooxygenase-2
  • Cytokines
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology
  • Physiology (medical)


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