tretinoin and Carbon-Tetrachloride-Poisoning

Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all-trans-retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation- or bleomycin-induced lung fibrosis.. We examined the impact of ATRA on carbon tetrachloride (CCl(4))-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-beta1 and interleukin (IL)-6 in CCl(4)-treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs.. CCl(4)-induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF-beta1, IL-6 and collagen from HSCs, (ii) TGF-beta-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-kappaB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-beta1 and IL-6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis.. Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.

Topics: Animals; Carbon Tetrachloride Poisoning; Cell Proliferation; Cell Transdifferentiation; Collagen; Hepatic Stellate Cells; Injections, Intraperitoneal; Interleukin-6; Liver; Liver Cirrhosis, Experimental; Mice; Mice, Inbred BALB C; NF-kappa B; p38 Mitogen-Activated Protein Kinases; RNA, Messenger; Transforming Growth Factor beta1; Tretinoin

We investigated the effect of transglutaminase (TGase) on in guinea pigs and rats. Serum alanine aminotransferase (ALT) level increased 1 d after CCl(4) treatment of both in guinea pigs and rats since TGaese activity was greatly higher in guinea pigs than rats. However, serum ALT level in guinea pigs was very much lower than that in rats. Liver TGase activities decreased after CCl(4) treatment in both guinea pigs and rats. However, TGase activities in the liver from guinea pigs were higher than that from rats. Decreased TGase activities by CCl(4) in the liver from guinea pigs and rats were significantly recovered by retinoic acid treatment that was reported to increase TGase. Degree of recovery of serum ALT level by retinoic acid in rats was larger than in guinea pigs. These results suggested that the distinction of the effect of retinoic acid on serum ALT level in CCl(4)-treated animals was due to the different TGase activity that increased membrane stability.

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Guinea Pigs; Male; Rats; Rats, Wistar; Species Specificity; Transglutaminases; Tretinoin

Transglutaminase (TGase) activity in the cytosol fraction of the mouse liver increased following intraperitoneal injection of retinoic acid. Retinoic acid inhibited the carbon tetrachloride-induced increase in serum alanine transaminase activity. These findings suggest that TGase is involved in the effect of retinoic acid on carbon tetrachloride-induced liver damage.

Topics: Alanine Transaminase; Animals; Calcium; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Cell Nucleus; Cytochrome P-450 Enzyme System; Cytochromes b5; Cytosol; Liver; Male; Mice; Mice, Inbred Strains; Transglutaminases; Tretinoin

A study was conducted to examine the inhibitory effect of acyclic retinoid (polyprenoic acid) on the secretion of alpha-fetoprotein (AFP) in rats with chronic liver damage induced by CCl4. Oral administration of the compound brought about a significant reduction of serum AFP levels at the time when liver cirrhosis was formed. Acyclic retinoid also decreased the activities of serum aminotransferases and ornithine carbamyl transferase, while it increased serum albumin levels, demonstrating the reduction of hepatic parenchymal damage. Significant negative correlation was observed between serum AFP and albumin levels. This cytoprotective effect of the retinoid on the parenchymal cell may well be related to the inhibition of the synthesis and/or secretion of AFP. No significant side effect was observed, despite a long-term administration of the compound. The present finding will provide a potential scope for the future use of acyclic retinoid for the treatment of chronic liver damage.

Topics: alpha-Fetoproteins; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Liver; Liver Diseases; Male; Ornithine Carbamoyltransferase; Rats; Rats, Inbred Strains; Serum Albumin; Tretinoin