Effects of phenobarbital upon triacylglycerol metabolism in the rabbit

1. The association between hepatic microsomal enzyme induction and triacylglycerol metabolism was examined in fasting male rabbits (2kg body wt.) injected intra-peritoneally with 50 mg of phenobarbital per kg for 10 days. 2. Occurrence of enzyme induction was established by a significant increase in hepatic aminopyrine N-demethylase activity and cytochrome P-450 content, as well as a doubling of microsomal protein per g of liver and a 54% increase in liver weight. Parallel increments in hepatic gamma-glutamyltransferase (EC 2.3.2.2) activity occurred; these were more pronounced in the whole homogenate than in the microsomes, which only accounted for 12.5% of the total enzyme activity in the controls and 17.0% in the animals given phenobarbital. Increased activity of gamma-glutamyltransferase activity was also observed in the blood serum of the test animals. 3. The rabbits given phenobarbital manifested increased hepatic triacylglycerol content and the triacylglycerol concentration of blood serum was also elevated. These changes were accompanied by a significantly enhanced ability of cell-free fractions of liver from the test animals (postmitochondrial supernatant and microsomal fractions) to synthesize glycerolipids in vitro from sn-[14C] glycerol 3-phosphate and fatty acids, when expressed per whole liver. Relative to the protein content of the fraction, glycerolipid synthesis in vitro was significantly decreased in the microsomes, presumably consequent upon the dramatic increase in their total protein content, whereas no change occurred in the postmitochondrial supernatant, possibly due to the protective effect of cytosolic factors present in this fraction and known to enhance glycerolipid synthesis. 4. Microsomal phosphatidate phosphohydrolase accounted for 85% of the total liver activity of this enzyme and its specific activity was 20-fold higher than that of the cytosolic phosphatidate phosphohydrolase (EC 3.1.3.4), when each was measured under optimal conditions. A significant increase in the activity of both enzymes per whole liver occurred in the rabbits given phenobarbital. A closer correlation between hepatic triacylglycerol content and and microsomal phosphatidate phosphohydrolase, as well as the above observation, suggest that this, rather than the cytosolic enzyme, may be rate-limiting for triacylglycerol synthesis in rabbit liver. 5. Significant correlations were observed between the various factors of hepatic microsomal-enzyme induction (aminopyrine N-demethylase and gamma-glutamyltransferase activity as well as cytochrome P-450 content) and hepatic triacylglycerol content, suggesting that that microsomal enzyme induction may promote hepatic triacylglycerol synthesis and consequently hypertriglyceridaemia in the rabbit.

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Effects of phenobarbital upon triacylglycerol metabolism in the guinea pig

Canadian Journal of Biochemistry ◽

10.1139/o81-007 ◽

1981 ◽

Vol 59 (1) ◽

pp. 48-53 ◽

Cited By ~ 9

Author(s):

David M. Goldberg ◽

Alexander Yu ◽

M. Waheed Roomi ◽

Daniel A. K. Roncari

Keyword(s):

Guinea Pig ◽

Enzyme Induction ◽

Guinea Pigs ◽

Microsomal Enzyme ◽

Triacylglycerol Metabolism ◽

Triacylglycerol Synthesis ◽

Hepatic Microsomal Enzyme ◽

Triacylglycerol Content ◽

Hepatic Triacylglycerol ◽

Microsomal Enzyme Induction

The association between hepatic microsomal enzyme induction and triacylglycerol metabolism was examined in fasting male guinea pigs injected intraperitoneally with 50 mg phenobarbital∙kg−1 for 7 days. Enzyme induction was established by a significant increase in hepatic aminopyrine N-demethylase activity, cytochrome P450 content, and hepatic γ-glutamyltransferase activity. Increased activity of γ-glutamyltransferase was also observed in the blood serum of treated animals. The phenobarbital-treated guinea pigs manifested increased hepatic triacylglycerol content and serum triacylglycerol concentration, accompanied by enhanced ability of cell-free fractions of liver to synthesize glycerolipids in vitro from sn-[14C]glycerol 3-phosphate and fatty acids. Microsomal phosphatidate phosphohydrolase accounted for 97% of the total liver activity of this enzyme, and its specific activity was 50-fold higher than that of the cytosolic enzyme when each was measured under optimal conditions. Activity of the cytosolic phosphohydrolase per liver doubled and that of the microsomal phosphohydrolase increased by 40% in the phenobarbital-treated guinea pigs. The microsomal, but not the cytosolic enzyme, showed a significant correlation with hepatic triacylglycerol content. Significant correlation was observed between the various parameters of hepatic microsomal enzyme induction and hepatic triacylglycerol content, suggesting that enzyme induction may promote triacylglycerol synthesis and consequent hypertriglyceridaemia in the guinea pig.

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Triacylglycerol metabolism in the phenobarbital-treated rat

Biochemical Journal ◽

10.1042/bj1960337 ◽

1981 ◽

Vol 196 (1) ◽

pp. 337-346 ◽

Cited By ~ 18

Author(s):

David M. Goldberg ◽

M. Waheed Roomi ◽

Alexander Yu ◽

Daniel A. K. Roncari

Keyword(s):

Enzyme Induction ◽

Diacylglycerol Acyltransferase ◽

Female Rats ◽

Male Rats ◽

Microsomal Enzyme ◽

Triacylglycerol Metabolism ◽

Triacylglycerol Content ◽

Hepatic Triacylglycerol ◽

Microsomal Enzyme Induction

1. Various aspects of triacylglycerol metabolism were compared in rats given phenobarbital at a dose of 100mg/kg body wt. per day by intraperitoneal injection; controls were injected with an equal volume of 0.15m-NaCl by the same route. Animals were killed after 5 days of treatment. 2. Rats injected with phenobarbital demonstrated increased liver weight, and increased microsomal protein per g of liver. Other evidence of microsomal enzyme induction was provided by increased activity of aminopyrine N-demethylase and cytochrome P-450 content. Increased hepatic activity of γ-glutamyltransferase (EC 2.3.2.2) occurred in male rats, but not in females, and was not accompanied by any detectable change in the activity of this enzyme in serum. 3. Phenobarbital treatment increased the hepatic content of triacylglycerol after 5 days in starved male and female rats, as well as in non-starved male rats; non-starved females were not tested in this regard. At 5 days after withdrawal of the drug, there was no difference in hepatic triacylglycerol content or in hepatic functions of microsomal enzyme induction between the treated and control rats. 4. After 5 days, phenobarbital increased the synthesis in vitro of glycerolipids in cell-free liver fractions fortified with optimal concentrations of substrates and co-substrates when results were expressed per whole liver. The drug caused a significant increment in the activity of hepatic diacylglycerol acyltransferase (EC 2.3.1.20), but did not affect the activity per liver of phosphatidate phosphohydrolase (EC 3.1.3.4) in cytosolic or washed microsomal fractions. A remarkable sex-dependent difference was observed for this latter enzyme. In female rats, the activity of the microsomal enzyme per liver was 10-fold greater than that of the cytosolic enzyme, whereas in males, the activities of phosphohydrolases per liver from both subcellular fractions were similar. 5. The phenobarbital-mediated increase in hepatic triacylglycerol content could not be explained by a decrease in the hepatic triacylglycerol secretion rate as measured by the Triton WR1339 technique. Since the hepatic triacylglycerol showed significant correlation with microsomal enzyme induction functions, with hepatic glycerolipid synthesis in vitro and with diacylglycerol acyltransferase activity, it is likely to be due to enhanced triacylglycerol synthesis consequent on hepatic microsomal enzyme induction. 6. In contrast with rabbits and guinea pigs, rats injected with phenobarbital showed a decrease in serum triacylglycerol concentration in the starved state; this decrease persisted for up to 5 days after drug administration stopped, and did not occur in non-starved animals. It seems to be independent of the microsomal enzyme-inducing properties of the drug, and may be due to the action of phenobarbital at an extrahepatic site.

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Enzyme induction and hepatic glycerolipid synthesis in rats treated with 3-methlcholanthrene

Canadian Journal of Biochemistry ◽

10.1139/o81-109 ◽

1981 ◽

Vol 59 (9) ◽

pp. 793-798 ◽

Cited By ~ 2

Author(s):

D. M. Goldberg ◽

M. W. Roomi ◽

A. Yu ◽

D. A. K. Roncari

Keyword(s):

Enzyme Induction ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Male Rats ◽

Microsomal Enzyme ◽

Aryl Hydrocarbon ◽

Triacylglycerol Content ◽

Glycerolipid Synthesis ◽

Hepatic Triacylglycerol

Fasting male rats fed 3-methylcholanthrene in a daily dose of 40 mg∙kg body weight−1 gave evidence of hepatic microsomal enzyme induction after 3 days through significantly increased hepatic aryl hydrocarbon hydroxylase activity, cytochrome P448 content, and characteristic changes in microsomal proteins analysed by sodium dodecyl sulfate – polyacrylamide gel electrophoresis. Concomitantly, activities of aminopyrine N-demethylase and microsomal γ-glutamyltransferase, which are increased in phenobarbital-treated rats, significantly declined. In contrast to phenobarbital, which has been previously shown to increase hepatic triacylglycerol content and in vitro glycerolipid synthesis, 3-methylcholanthrene did not affect hepatic triacylglycerol content, but did inhibit glycerolipid synthesis by cell-free preparations of rat liver and significantly reduced serum triacylgiycerol concentration. Thus, the two prototypical drugs inducing characteristically different changes in microsomal enzyme and hemoprotein response also seem to differ in their effect upon another important microsomal function, hepatic glycerolipid synthesis.

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Factors That Affect the Induction of Gamma Glutamyltransferase in Epileptic Patients Receiving Anti-Convulsant Drugs

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328702400408 ◽

1987 ◽

Vol 24 (4) ◽

pp. 391-399 ◽

Cited By ~ 10

Author(s):

Solomon A Braide ◽

T J Davies

Keyword(s):

Enzyme Induction ◽

Drug Concentration ◽

Serum Drug Concentration ◽

Microsomal Enzyme ◽

Duration Of Treatment ◽

Serum Samples ◽

Gamma Glutamyltransferase ◽

Epileptic Patients ◽

Microsomal Enzyme Induction ◽

Convulsant Drug

Serum samples from 335 epileptic patients receiving one or more anticonvulsant drugs, phenobarbitone, primidone and phenytoin, have been analysed for biochemical liver profile (BLP) and serum drug concentration. The results show that the induction of serum gamma glutamyltransferase (GGT) is affected by the sex and age of the patient, type of anti-convulsant drug prescribed and duration of treatment. It is less affected by serum drug concentration. It is suggested that these factors must be considered when interpreting results involving serum GGT activity as the index of microsomal enzyme induction.

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