Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males

Abstract

It is known that women develop hepatic injury more rapidly and with exposure to less ethanol than men; however, mechanisms remain unclear. The purpose of this study was to determine if an enteral alcohol delivery model could be used to study susceptibility of females to alcohol-induced liver injury. Male and female Wistar rats (age- or weight-matched) were given ethanol (11-12 g.kg-1.day-1) continuously for up to 4 wk via intragastric feeding, and control rats received a high-fat diet without ethanol. There were no significant differences in body weight among the groups studied. Furthermore, mean ethanol concentrations, their cyclic pattern in urine, and rates of ethanol elimination were also not different between the genders under these conditions. Ethanol treatment elevated serum aspartate aminotransferase levels in male rats to 126 +/- 10 IU/l after 4 wk. In females, however, values increased more rapidly and reached significantly higher values at 4 wk (168 +/- 18 IU/l). Steatosis, inflammation, and necrosis assessed histologically also developed more rapidly and were more severe in females than males. Steatosis due to ethanol exposure, which was localized in centrilobular areas in males, was panlobular in the female. Moreover, endotoxin in plasma, intercellular adhesion molecule 1 expression in hepatic sinusoidal-lining cells, and the number of infiltrating inflammatory cells in the liver were 2-2.5-fold greater in females than males. These changes possibly account for increased hepatic injury due to ethanol in the female.

Effect of Chronic Coadministration of Endotoxin and Ethanol on Rat Liver Pathology and Proinflammatory and Anti–Inflammatory Cytokines

“…30 However, the levels of circulating endotoxin that were needed (200-500 pg/mL) were 20 to 50 times higher than those found in our ethanol-treated animals (mean, 9.3 pg/mL) and 6 to 10 times higher than after ethanol feeding by the intragastric model (30-70 pg/mL). 8,31 Remarkably, this dose of endotoxin did not significantly enhance steatosis and focal inflammation in ethanol-fed animals. Previous studies, based on both animal experiments 8,31 and clinical observations, 4 have suggested aggravation of ALD by circulating endotoxin.…”

“…8,31 Remarkably, this dose of endotoxin did not significantly enhance steatosis and focal inflammation in ethanol-fed animals. Previous studies, based on both animal experiments 8,31 and clinical observations, 4 have suggested aggravation of ALD by circulating endotoxin. Endotoxin by itself caused occasional polymorphic inflammation, particularly in the sinusoids.…”

Mechanisms of alcohol-induced hepatotoxicity: studies in rats

“…Plasma endotoxin levels were more than 2-fold higher in females than males following ethanol feedng and ICAM-1 expression in hepatic endothelial cells was also about 2-fold greater in females than males. Thus, a new model to study female susceptibility to alcoholic hepatitis has been developed (13). Initial work with this model fits the idea that endotoxin and Kupffer cells are responsible for the increased susceptibility of women to alcohol compared to men.…”

“…Radical adducts are substituted nitroxide free radicals, which tend to be relatively long-lived compared to free radicals which are very transient in biological systems. POBN radical adducts characteristically exhibit a six-line ESR spectrum (figure 1A), while 13 C substitution on the alpha-carbon of a spin-trapped species causes six additional lines due to the magnetic interaction of the 13 C with the unpaired electron. The subsequent production of a 12-line spectrum after administration of 13 C ethanol provides unequivocal physical evidence that the trapped radical arises from the labeled parent ethanol.…”

“…POBN radical adducts characteristically exhibit a six-line ESR spectrum (figure 1A), while 13 C substitution on the alpha-carbon of a spin-trapped species causes six additional lines due to the magnetic interaction of the 13 C with the unpaired electron. The subsequent production of a 12-line spectrum after administration of 13 C ethanol provides unequivocal physical evidence that the trapped radical arises from the labeled parent ethanol. Computer simulation of such an ESR spectrum gives spectral parameters called "hyperfine coupling constants" which can be compared with values of well-characterized radical adducts.…”