Asunto(s)
Alprostadil/uso terapéutico , Endotelina-1/sangre , Trasplante de Hígado/métodos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Perros , Femenino , Hepatectomía/métodos , Pruebas de Función Hepática , Trasplante de Hígado/patología , Trasplante de Hígado/fisiología , Masculino , Recolección de Tejidos y Órganos/métodos , Trasplante Homólogo/métodos , Trasplante Homólogo/patología , Trasplante Homólogo/fisiologíaRESUMEN
BACKGROUND/AIMS: In most patients with chronic viral hepatitis the predominant lobular location of hepatic necrosis and fibrosis is the periportal zone. We established a new simple model of hepatic fibrosis in rats by repetitive periportal necrosis with allylalcohol. METHODS: Of 40 male adult rats, 30 were injected with 0.62 mmol/kg of allylalcohol intraperitoneally twice a week, the remaining 10 with normal saline as controls. Ten rats were killed at each of 4, 8, and 16 weeks later. The extent of fibrosis was evaluated according to the portal-portal extent. Transforming growth factor (TGF) beta1 mRNA in liver tissues was detected by reverse transcriptase polymerase chain reaction, and its levels were determined by the endpoint titers of serial two-fold dilutions of cDNA. RESULTS: After 4 weeks, periportal fibrosis was produced in only 6 out of 10 rats, and was mild in extent. However, after 8 weeks, 8 out of 9 survivors showed moderate to severe fibrosis, which corresponded to a score of 7 or more. The extent of fibrosis correlated significantly with the amount of collagen and TGFbeta1 mRNA expression in liver tissues. The collagen content and expression of TGFbeta1 mRNA were also upregulated significantly in liver tissues with a fibrosis score of 7 or more. CONCLUSIONS: Hepatic fibrosis can be sufficiently induced by repetitive intraperitoneal injection of 0.62 mmol/kg of allylalcohol twice a week for 8 weeks. This simple model of hepatic fibrosis, in which TGFbeta1 is overexpressed at the transcriptional level, may be useful in the study of patients who have predominantly periportal necrosis and fibrosis.
Asunto(s)
Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/patología , Hígado/patología , Propanoles , Animales , Masculino , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
OBJECTIVES: The hepatotoxicity of acetaminophen is not a result of the parent compound but is mediated by its reactive metabolite N-acetyl-p-benzoquinone imine. Cytochrome P4502E1 (CYP2E1) is the principal enzyme of this biotransformation, which accounts for approximately 52% of the bioactivation in human microsomes. Recently, chlormethiazole a sedative drug, is reported to be an efficient inhibitor of CYP2E1 activity in human beings. In this study we wished to evaluate whether chlormethiazole, an inhibitor of CYP2E1, could prevent acetaminophen-induced liver injury in mice. METHODS: Acetaminophen, at doses ranging from 200 to 600 mg/kg, was injected into the peritoneum of female C57BL/6 inbred mice fasted for four hours. Chlormethiazole (60 mg/kg) or 5% dextrose water was given 30 min before or 2 h after acetaminophen. Serum aminotransferase activities, histologic index score, survival rate and hepatic malondialdehyde levels were compared. RESULTS: Pretreatment with chlormethiazole 30 min before 400 mg/kg of acetaminophen completely inhibited acetaminophen-induced liver injury (median 118.5 U/L, range 75 to 142 vs. 14,070 U/L, range 5980 to 27,680 for AST; 49 U/L, range 41 to 64 vs. 15,330 U/L, range 13,920 to 15,940 for ALT). In mice receiving chlormethiazole 2 h after acetaminophen, the mean AST and ALT levels were also less elevated, reaching only 20% of the value of acetaminophen-only group. These protective effects were confirmed histologically. Whereas more than 50% of mice died at 500 mg/kg of acetaminophen, all the mice pretreated with chlormethiazole survived at the same dose. CONCLUSION: Chlormethiazole effectively reduces acetaminophen-induced liver injury in mice. Further studies are needed to assess its role in humans.