Enhanced lipid peroxidation in hepatic cirrhosis.
Pratico D. Iuliano L. Basili S. Ferro D. Camastra C. Cordova C. FitzGerald GA. Violi F.
Istituto di Clinica Medica I, University La Sapienza, Rome, Italy.
BACKGROUND: Lipid peroxidation is thought to play a role in the evolution of liver damage, based on evidence in experimental models. However, evidence that lipid peroxidation occurs in patients with liver disease remains to be provided. We addressed the hypothesis by measuring levels of 8-epi Prostaglandin F2 alpha a bioactive prostaglandin isomer produced by free radical catalyzed peroxidation of arachidonic acid, in patients with liver cirrhosis. METHODS: In 42 patients with hepatic cirrhosis 8-epi Prostaglandin F2 alpha, factor VII activity, endotoxemia, carotenoids and alpha-tocopherol were measured. In 10 patients 8-epi Prostaglandin F2 alpha was also measured before and 30 days after 300 mg b.i.d. vitamin E administration. RESULTS: Cirrhotic patients had significant higher 8-epi Prostaglandin F2 alpha, excretion than controls [median (range): 199.2 (60.0-812) vs 85.9 (55.6-160.0) pg/mg creatinine, p < 0.0001]. Patients with urinary 8-epi Prostaglandin F2 alpha above the range in controls were more likely to have moderate or severe than mild liver failure (p < 0.004). They also had lower factor VII activity (62 +/- 19 vs 74 +/- 15%, P < 0.02) than patients with normal levels of the isoprostane. Urinary excretion of 8-epi Prostaglandin F2 alpha correlated directly with endotoxemia (Rho = 0.56, p < 0.0002) and inversely with factor VII (Rho = -0.39, p < 0.02). Cirrhotic patients given vitamin E showed a significant decrease of urinary 8-epi Prostaglandin F 2 alpha [median (range): 342.5 (170 - 812) vs 292.5 (142-562) pg/mg creatinine, p < 0.04]. CONCLUSION: This study demonstrated that lipid peroxidation is increased in vivo in patients with cirrhosis and suggests that oxidant stress might contribute to the deterioration of liver disease.
Acetaldehyde inhibits chymotrypsin and serum anti-chymotrypsin activity.
Brecher AS. Yang MP.
Department of Chemistry, Bowling Green State University, OH 43403, USA.
BACKGROUND: Chymotrypsin (CT) and CT-like enzymes contribute to the dynamics of metabolism by their participation in digestion, peptide hormone generation and catabolism, fertilization of ova and inhibition of thrombin-induced platelet aggregation, among other processes. The frequency of pancreatitis is observably higher in alcoholics, and pancreatic enzymes have been associated with localized vascular damage, thrombosis and pancreatic necrosis. METHODS: Since CT is a major pancreatic enzyme and may serve as a link between pancreatitis, coagulopathy, and alcoholism, the affect of acetaldehyde (AcH) the primary metabolite of ethanol, upon the enzyme and upon the influence of human serum thereon was studied. RESULTS: It was observed that CT activity upon glutaryl-L-phenylalanine-b-naphthylamide was inhibited to the extent of 23.7%, 52.5%, and 96.7% by 44.7, 89.4, and 447 mmol/L AcH in a fluorometric assay whereby the enzyme was dialyzed to remove excess AcH prior to assay. The p values were < 0.04. Aliquots of human serum (10 microL, 20 microL, 30 microL, 40 microL, 50 microL, and 100 microL) inhibited 40 micrograms of CT by 13%, 37.7%, 65.3%, 89.8%, and 92.8%, respectively (n = 6; p = < 0.05). The serum did not hydrolyze the fluorogenic substrate. On the other hand, AcH added to serum at 447, 224, 112, or 56 mmol/L resulted in 42.6%, 42.6%, 52.9%, and 60.3% inhibition of CT relative to a 69.1% inhibition of the enzyme by serum alone (n = 6; = p < 0.01). CONCLUSIONS: These data show that AcH clearly decreases the antichymotryptic activity of serum (consisting of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and alpha 2-macroglobulin). The incomplete inactivation of chymotrypsin by serum and partial inactivation of CT inhibitor(s) by AcH suggest the possibility that CT leaked into the circulation, (in alcoholic pancreatitis) may be available in blood to lower the clotting potential induced by thrombin-activated platelets, and that a greater amount of CT might be available in the blood of alcoholics, thereby contributing, in part, to the prolongation of clotting times.