The influence of diets containing from 0 to 81 per cent of protein on tolerated doses of pesticides

Krijnen, C. J.; Boyd, Eldon M.

doi:10.1016/0010-4035(71)90032-2

Cited by 21 publications

(3 citation statements)

References 5 publications

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“…Dietary alterations can affect hepatic microsomal enzyme activity (6,7,15,17,26), but these types of dietary change do not apply in our study since our rats received diets identical in amounts of calories, protein and carbohydrate. Likewise, nutritional deficiencies cannot explain the fatty infiltration of the liver that we observed.…”

Section: Discussionmentioning

confidence: 90%

“…Composition of the diet can also influence the biologic fate, and therefore the intensity and duration of action of drugs (6,7). Reduction in dietary protein decreases rates o f metabolism of some drugs, whereas a high protein diet in creases these rates (15,17). Strother et al (26) first showed that high dietary carbohydrates decreases hepatic metabolism of drugs both in vitro and in vivo.…”

mentioning

confidence: 99%

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Effects of Chronic Parenteral Carbohydrate Administration on Hepatic Drug Metabolism in the Rat

Lm²,

et al. 1979

Pharmacology

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Effects of chronic parenteral carbohydrate administration on hepatic microsomal enzyme activity were studied in the rat. Intraperitoneal injections of either glucose or fructose (2.88 g daily for 7 days) significantly decreased hepatic cytochrome P-450 content and ethyl-morphine N-demethylase and aniline hydroxylase activities. By the 5th day, cytochrome P-450 content decreased to 70-76% and ethylmorphine N-demethylase activity to 66–69% of control values. Aniline hydroxylase activity was not significantly altered until the 7th day, by which time it was 77–79% of control values. In vivo assessment of hepatic drug-metabolizing capacity using antipyrine as a test drug confirmed these decreases observed in vitro. Two major conclusions of these experiments are that such variables as time and dose of carbohydrate administration can affect the magnitude of the changes produced and that each parameter measured exhibited a distinctive pattern of change with time. Chronic carbohydrate administration produced hepatic fatty infiltration and glycogen depletion. Since all groups received identical amounts of specific nutrients, fatty infiltration was probably due to increased lipogenesis with decreased hepatic oxidative metabolism of fat. During these experiments neither hypoinsulinemia nor increased levels of cyclic AMP were observed. The molecular mechanisms responsible for hepatic glycogen depletion and decreased MFO activities remain to be established.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

Effects of Chronic Parenteral Carbohydrate Administration on Hepatic Drug Metabolism in the Rat

Lm²,

et al. 1979

Pharmacology

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“…Since then, many laboratories have shown that protein deficiency decreases the microsomal oxidation rates of a great variety of drugs and other foreign chemicals (2-4). Boyd and his colleagues (5,6) observed that many pesticides indicated increased toxicity in protein-depleted animals, as illustrated by a 2,100-fold increase in the toxicity of captan (5). In contrast, some compounds such as carbon tetrachloride (7) and heptachlor (8) have shown lower toxicities.…”

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confidence: 99%

Effect of Dietary Protein Deficiency on Rat Hepatic Drug-Metabolizing Enzyme System

Kawano

Hiraga

1980

Japanese Journal of Pharmacology

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Abstract-Wehave examined the effect of dietary protein deficiency on rat hepatic drug-metabolizing enzyme system for a period of two months. Cytochrome P-450 and b5 contents in liver microsomes, which were plotted on semilogarithmic paper as a function of the time of deficiency, showed biphasical reductions during protein deficiency: rapid decreases in the first 3 weeks were followed by more gradual decreases. However, the three enzymatic activities examined, i.e. aminopyrine demethylase, aniline hydroxylase and p-nitroanisole demethylase, were not reduced at a uniform rate. In the earlier phase, activities of the former two enzymes were reduced more rapidly than that of the last phase. This biphasical and non-uniform reduction of enzymatic activities suggests the existence of two or more cytochrome P-450 subspecies in nondepleted male rats. Intraperitoneal administration of well-known environmental pollutants, polychlorinated dibenzofurans and biphenyls (100 fig and 100 mg/kg, respectively) to the depleted rats resulted in a marked induction of drug-metabolizing enzymes. However, as the deficiency became more severe (2 months), the induction declined to a considerable degree, especially in the case of polychlorinated biphenyl administration.In 1952, V.A. Drill presented a review concerning the interaction between hepatotoxins and dietary factors, in which he showed that protein deficiency affected the toxicity of the various hepatotoxins (1). Since then, many laboratories have shown that protein deficiency decreases the microsomal oxidation rates of a great variety of drugs and other foreign chemicals (2-4). Boyd and his colleagues (5, 6) observed that many pesticides indicated increased toxicity in protein-depleted animals, as illustrated by a 2,100-fold increase in the toxicity of captan (5). In contrast, some compounds such as carbon tetrachloride (7) and heptachlor (8) have shown lower toxicities. These increased or decreased toxicities observed in protein-depleted animals are generally interpreted to be caused by the depression of foreign chemical metabolism during protein deficiency.In the last decade, several investigators suggested that different forms of cytochrome P-450 existed in liver microsomes, and their arguments were actually proved by the purification of several cy tochrome P-450 and P-448 subspecies different in spectral properties, minimal molecular weight, substrate specificities or immunological properties (9).In the present report we have examined the time course of the decrease of rat hepatic hemoprotein contents and drug-oxidation activities during protein deficiency, and obtained results suggesting that different cytochrome P-450 subspecies were reduced at very different rates. We have also examined the induction of these enzymes caused by polychlorinated

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Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet I. Changes in drug enterohepatic circulation

McAnena

Rossi

Mehta

et al. 1987

Cancer

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Severe enteritis and death consistently occur within 150 hours of a single intraperitoneal dose of 25 mg/kg methotrexate given to rats fed an elemental diet. Rats fed a regular chow diet show no clinical evidence of gastrointestinal morbidity or mortality at this dose. The etiology of this enhanced toxicity is not clear, however. It this study rats were randomized to receive an elemental diet (n = 45) or a regular chow diet (n = 45) for 7 days. They were then given a bolus dose of 3H methotrexate (25 mg/kg) intraperitoneally. At 20 and 40 minutes and at 1, 2, 12, 24, 48, 72, and 96 hours after injection, five animals from each group were anesthetized, and mean methotrexate levels in bile and serum, and tissue methotrexate concentrations in proximal, mid, and distal small intestine and in liver were obtained. Mean methotrexate levels in bile were significantly elevated in rats fed an elemental, chemically defined diet at 12, 24, 48, and 72 hours compared with regular diet fed rats. Mean serum methotrexate levels were elevated in both the inferior vena cava (IVC) and portal vein (PV) at 12 (IVC), 24 (PV), and 48 hours (IVC) in elemental, liquid diet fed rats. There were no statistical differences between methotrexate levels in rats fed an elemental diet or a regular chow diet in proximal or mid small intestine at any of the time points measured. In the distal small intestine, methotrexate levels were significantly elevated at 24 hours in rats fed an elemental, chemically defined liquid diet (P less than 0.03) compared with regular diet fed rats. Methotrexate levels in liver of rats fed an elemental, chemically defined liquid diet were significantly elevated at 24 and 48 (P less than 0.05) hours. Administration of an elemental, chemically defined liquid diet prolongs the enterohepatic circulation of methotrexate in rats and delays clearance of the drug from the systemic circulation. Thus, prolonged exposure of methotrexate to the cells of the intestinal mucosa explains the increased gastrointestinal side effects of the drug in rats fed an elemental, chemically defined liquid diet. If these results are applicable to man, elemental, chemically defined liquid diets are contraindicated as the sole nutritional source in patients receiving methotrexate. Such qualitative alteration of dietary intake may be a factor in the unpredictability of gastrointestinal side effects associated with high dose methotrexate administration.

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The influence of diets containing from 0 to 81 per cent of protein on tolerated doses of pesticides

Cited by 21 publications

References 5 publications

Effects of Chronic Parenteral Carbohydrate Administration on Hepatic Drug Metabolism in the Rat

Effects of Chronic Parenteral Carbohydrate Administration on Hepatic Drug Metabolism in the Rat

Effect of Dietary Protein Deficiency on Rat Hepatic Drug-Metabolizing Enzyme System

Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet I. Changes in drug enterohepatic circulation

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