Anthony J. Barak

Effect of phenobarbital on lipid peroxidation in the liver

Abstract It has been established that the administration of phenobarbital to rats produces an accumulation of triglyceride in the liver. In the present study, it has been demonstrated that phenobarbital increases hepatic lipid peroxidation as reflected by the observed diene conjugation absorption of microsomal lipids as well as the increase in malonic dialdehyde formation. Both the fatty infiltration and the lipoperoxidation were found to be inhibited by an antioxidant. N, N′-diphenyl-p-phenylenediamine. These data suggest that the peroxidative process may play a role in the phenobarbital-induced fatty liver.

Interaction of methotrexate with lipotropic factors in rat liver

Abstract Methotrexate (MTX), a drug used in cancer chemotherapy and in the treatment of psoriasis, is known to impair DNA and RNA synthesis by antagonizing folate metabolism. A major side-effect of this drug is the formation of a fatty liver and eventual cirrhosis of the liver. Since levels of certain lipotropic substances in the liver are also synthesized de novo by way of folate-dependent 1-carbon metabolism, this study was conducted to determine if the side-effects of MTX may be a consequence of interference with 1-carbon metabolism in the liver. This study investigated the effect of MTX on hepatic and serum lipidd content when various lipotropes were administered to rats fed a diet deficient in methionine, choline and vitamin B 12 . Results demonstrate that MTX can potentiate a choline-deficient fatty liver and block the lipotropic effect of vitamin B 12 . They also show that methionine and choline, products of 1-carbon metabolism beyond folate involvement, overcame the detrimental effects of MTX. This suggests that MTX interferes with hepatic methyl group genesis and hence blocks the de novo synthesis of methionine and choline.

57 – Defects in Methionine Metabolism: Its Role in Ethanol-induced Liver Injury

This chapter reviews the negative effects of ethanol in multiple steps in methionine metabolism that may lead to liver injury. Alcoholic liver disease is a major health care problem and ethanol consumption is reported to predominantly inhibit the activity of two vital cellular enzymes, methionine synthase and methyl adenosyhransferase involved in remethylating homocysteine and generating S-adenosylmethionine, respectively. By compensation, ethanol increases the activity of the enzyme betaine homocysteine methyltransferase that catalyzes an alternate pathway in methionine metabolism and utilizes hepatic betaine to remethylate homocysteine to form methionine and maintain levels of S-adenosylmethionine, the key-methylating agent. This is true in rat species that generate betaine from choline via choline oxidase. Extended periods of ethanol feeding however, is unable to maintain this alternate pathway. This results in a decrease in the hepatocyte level of S-adenosylmethionine and the most important cellular antioxidant, glutathione and increases in two toxic metabolites, homocysteine and S-adenosylhomocysteine. These changes in the various metabolites of methionine metabolism in turn result in serious functional consequences. These include decreases in the essential methylation reactions by inhibiting various methyhransferases, especially phosphatidylethanolamine methyhransferase, and direct toxicity to hepatocytes and stellate cells.

Phenobarbital-Induced Fatty Livers in the Rat

Summary Administration of phenobarbital to rats fed a standard laboratory diet or 6 different synthetic diets produced elevated levels of triglyceride, phospholipid and total cholesterol in the livers of these animals. By varying the choline, fat, and protein constituents in these diets it appears that choline and fat content are factors influencing the amount of triglyceride accumulating in livers as a result of phenobarbital administration. These dietary factors, however, did not appear to regulate the manner in which phenobarbital elevated phospholipid and total cholesterol levels.

Effects of phenobarbital administration on levels of physiological antioxidants in rat liver

Administration of phenobarbital to rats over a period of 5 days was shown to increase hepatic lipid peroxidation concomitant with induction of cytochrome P-450 and cytochrome c reductase. The purpose of this study was to determine whether the increase in lipid peroxidation was due to a lowering in hepatic antioxidants. The results show that increased lipid peroxidation was not due to a decreased level of antioxidants since the fat-soluble antioxidants were unchanged and ascorbate, a water-soluble antioxidant, was elevated. The relationship of the increase in hepatic ascorbate to enhanced lipid peroxidation is discussed.

Hepatic and Serum Lipid Patterns During Development of Phenobarbital Induced Fatty Livers in Rats

Summary Lipids were measured in the livers and sera of rats that had received phenobarbital injections for 3 days and 5 days. The same lipid patterns including free cholesterol, cholesterol esters, phospholipids, triglyceride and fatty acids were determined in the livers and sera of rats 3 days and 5 days following withdrawal of the drug. Liver lipids increased with time while the rats were injected with phenobarbital and decreased toward normal levels once the drug was withdrawn. During phenobarbital administration as well as during withdrawal the serum lipid levels did not change. These results suggest that decreased lipid transport and enhanced lipid mobilization may not play major roles in the induction of the phenobarbital fatty liver.

Effect of spinal cord transection on plasma and hepatic levels of certain essential elements and vitamins in rats

Abstract This study was conducted to determine whether spinal cord transection produces nutritional deficiency states in certain essential elements and water soluble vitamins in the rat. Spinal cords of female rats were severed at the T-9 level and these animals were matched and pair-fed to control animals that had undergone sham surgery. Following periods of 60, 90 and 180 days, animals were sacrificed and their plasma and livers assayed for selenium, manganese, zinc and magnesium and eight water soluble vitamins. The results indicate that spinal cord injury did not cause deficiencees in those nutrients studied. Instead the cord transection produced accumulations in the liver of all the elements and six of the vitamins studied. No explanation for these accumulations is known at this time.

Effects of Nicotinic Acid on Induction of Hepatic Drug Metabolizing Enzymes by Chronic Ethanol Administration

Summary The content of cytochrome P-450 and activities of aniline hydroxylase and glucose-6-phosphatase were determined in the livers of rats fed ethanol and nicotinic acid singly and in combination for 4 weeks. Similar determinations were conducted in livers from rats administered phenobarbital and nicotinic acid alone and in combination for 4 weeks. Both chronic ethanol feeding and phenobarbital administration increased the content of cytochrome P-450 and aniline hydroxylase activity. Glucose-6-phos-phatase activity was elevated by ethanol feeding but not by phenobarbital. Nicotinic acid treatment increased the content of cy-tochrome P-450 and aniline hydroxylation in the ethanol-treated but not in the control or phenobarbital-treated animals. Nicotinic acid did not influence the activity of glucose-6-phosphatase in either the ethanol- or phenobarbital-treated rats. The results of this study are consistent with the existence of a unique cytochrome P-450 which is induced by ethanol feeding, and the induction of this hemoprotein is further enhanced by the concomitant administration of nicotinic acid with ethanol.

Inability of selenium to affect creatine metabolism in rat muscle.

1. Two groups of adult rats were placed in a metal-free environment and pair-fed with selenium-supplemented and Se-deficient diets. 2. After 5 months the animals were killed and skeletal muscle concentrations of creatine, creating phosphate, ATP, protein and Se were determined. 3. Se deficiency was indicated by the low Se content of the skeletal muscle from the deficient animals, but no changes were found in the amounts of the other components. 4. These results suggest that Se may not be involved in creatine metabolism and that Se deficiency may not be concerned independently in the development of nutritional dystrophy, where changes are found in the levels of protein, creatine, creatine phosphate and ATP.

Effect of Phenobarbital on Choline Uptake in the Isolated Perfused Rat Liver

Experiments measuring hepatic choline uptake in the isolated perfused liver have demonstrated that phenobarbital inhibits this mechanism by 50 %. This inhibition was found to be dos