Modulation of Hepatic Glutamate Transporters by MC-100093 in Male and Female Alcohol-Preferring Rats Exposed to Ethanol

Background/Objective: Prolonged ethanol use can induce behavioral and physiological alterations and impair the liver’s capacity to metabolize ethanol, leading to hepatocyte injury. The spectrum of this disease ranges from fat accumulation to severe liver damage, including alcohol-related hepatitis and cirrhosis. MC-100093, a beta-lactam non-antibiotic compound, is known to modulate glutamate transporter-1 (GLT-1) and reduce ethanol drinking. Therefore, this study examined the effects of two optimal doses of MC-100093 on ethanol consumption and, consequently, ethanol-induced hepatic injury in both male and female alcohol-preferring (P) rats. Methods: Animals were divided into four groups and exposed to ethanol for six weeks. In week six, rats received intraperitoneal injections of saline, 100 mg/kg MC-100093, or 150 mg/kg MC-100093 for five consecutive days. Liver tissue samples were analyzed to assess GLT-1 and the cystine/glutamate antiporter (xCT), triglyceride levels, collagen type-1 (COL-1) deposition, and inflammatory cytokines. Results: MC-100093 effectively attenuated ethanol-induced liver damage by decreasing ethanol intake and restoring GLT-1, xCT, and COL-1 levels in the livers of both male and female P rats. Moreover, MC-100093 reversed ethanol-induced inflammation and reduced hepatic triglyceride levels. Conclusions: Our data show that MC-100093 effectively mitigates ethanol-induced liver injury.