Metabolic Interactions Among Environmental Chemicals and Drugs

Conney, Allan H.; Burns, J. J.

doi:10.1126/science.178.4061.576

Cited by 245 publications

(10 citation statements)

References 176 publications

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“…Effects of chronic and acute oral doses of chlorinated hydrocarbons have been observed on lipid metabolism (Conney and Burn, 1972).…”

mentioning

confidence: 99%

Changes in lipid profiles of liver microsomes of rats following intratracheal administration of DDT or endosulfan

Narayan¹,

Dani²,

Misra³

1990

J. of Env. Sc. & Hlth., Part B

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The effect of intratracheal administration of DDT (5 mg/100 g body weight) or endosulfan (1 mg/100 g body weight) to rats for three consecutive days, has been studied on liver lipid metabolism. The administration of DDT but not endosulfan significantly increased the liver weight and the microsomal protein contents. Both DDT and endosulfan treatments significantly increased the contents of microsomal phosphatidylcholine (PC), total-free- and esterified cholesterol. The distribution of unsaturated fatty acids of microsomal PC and PE was increased by DDT treatment. The intratracheal administration of DDT caused fatty infiltration of liver which was probably due to increased synthesis of triglycerides (TG). This is supported by the increased incorporation of radioactive palmitate-1-14C into microsomal TG. However, the increased incorporation of palmitate-1-14C into microsomal PC and phosphatidylethanolamine (PE) after the DDT treatment, was due to the increased transacylation reaction supported by the decreased activity of microsomal phospholipase A. The intratracheal administration of endosulfan did not have pronounced effect on liver fatty infiltration, or transacylation reaction in microsomal PC and PE. However, the results have shown that the treatments of DDT or endosulfan increased the PC contents and the incorporation of radioactive [methyl-3H]choline into PC of microsomes, resulting the increased synthesis of PC via CDPcholine pathway. Thus, the intratracheally administered DDT or endosulfan to rats showed that both the insecticides cause manifestations in the biochemistry of microsomal membrane lipids, although the effects of DDT being more pronounced. Therefore, the translocation effects of these insecticides or metabolites from lung to liver is established.

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“…Effects of chronic and acute oral doses of chlorinated hydrocarbons have been observed on lipid metabolism (Conney and Burn, 1972).…”

mentioning

confidence: 99%

Changes in lipid profiles of liver microsomes of rats following intratracheal administration of DDT or endosulfan

Narayan¹,

Dani²,

Misra³

1990

J. of Env. Sc. & Hlth., Part B

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“…Drug studies were also carried out immediately prior to the start of the test diet study (home diet-1) as well as on the 10th and 14th days (home diet-2) after the test diets. CHO, carbohydrate; PRO, protein. inhibited by drugs, hormones, and a variety of environmental agents (21). The interaction of environmental chemicals with this system has been extensively investigated, both in man and experimental animals.…”

mentioning

confidence: 99%

Interactions between nutritional factors and drug biotransformations in man.

Alvares¹,

Anderson²,

Conney³

et al. 1976

Proc. Natl. Acad. Sci. U.S.A.

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This study was undertaken to examine the influence of nutritional factors on the activity of the mixed function oxidase system in man, which is cytochrome P450 dependent. Three normal volunteers were fed a low carbohydrate-high protein diet for 2 weeks, followed by a high carbohydrate-low protein diet for the following 2 weeks. At the end of each test diet period, the plasma elimination rates of antipyrine and theophylline were determined. The mean plasma half-life for antipyrine was 17.5 hr on the high carbohydrate-low protein diet and 9.2 hr on the low carbohydrate-high protein diet. The mean plasma half-life for theophylline was 8.9 hr on the high carbohydrate-low protein diet and 5.9 iwr on the low carbohydrate-high protein diet. These data demonstrate marked influences of dietary carbohydrate and/or protein ingestion on oxidative biotransformation of drugs in man. The effects of changes in dietary macronutrient composition on the hepatic microsomal enzymes that metabolize drugs, other foreign chemicals, and endogenous compounds, such as steroid hormones, have been studied extensively in animals (1). These studies show that dietary macronutrient composition, as well as the presence of contaminants and food additives, can influence the activities of these enzymes. Although dietary composition has been shown to be an important environmental determinant in the response of the experimental animal to pharmacological agents, such studies are lacking in man. A significant proportion of normal subjects manipulate their diets in weight-reducing regimens. Similarly, dietary treatments in clinical conditions, including obesity, atherosclerosis, and diabetes, are considered to play a significant role in the management of such disease problems. It is the purpose of these studies to show that nutritional-pharmacological interactions can occur in normal individuals when macronutrient composition of the diet is altered.In animals, in relation to hepatic microsomal enzyme activities, the dietary constituent most studied is protein. A reduction in dietary protein intake has been shown to decrease microsomal oxidations of various substrates, such as pentobarbital, aminopyrine, and zoxazolamine (2), and to increase the toxicity of foreign compounds, such as drugs (2) and pesticides (3, 4). The decreases in microsomal oxidations are accompanied by decreases in hepatic content of the hemeprotein cytochrome P-450, the terminal oxidase of the hepatic mixed function oxidase system. In contrast, the metabolism of the drugs indicated is increased in rats fed a high protein diet (2). A high carbohydrate intake has been shown to increase barbiturate-induced sleeping time in mice (5), to cause cessation of lipid peroxidase activity, and to cause a considerable decrease in liver mixed function oxidase activity in rats (6). A specific lipid role in the mixed function oxidase system was first demonstrated by Strobel et al. (7), who established the requirement for phosphatidylcholine in a reconstituted mixed function oxidase system. ...

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“…Presently, it appears to be well established that while most chemical carcinogens do not act as the ultimate carcinogenic molecule; they do yield, with metabolic transformation, intermediates with mutagenic and neoplastic activity (Magee and Swann, 1969;Parke and Williams, 1969;Conney and Burns, 1972;Irving, 1973;Hart et al, 1978;Brusick, 1977). Data from a number of mutagen test systems that employ either microsomal homogenates or feeder cells indicate that there is approximately a 90% correlation between carcinogenicity and mutagenicity and, where examined, unscheduled DNA synthesis (Huberman et al, 1971;Clive et al, 1972;Brookes et al, 1973;Duncan and Brookes, 1973;Huberman and Sachs, 1974;Krahn and Heidelberger, 1975;Huberman et al, 1975;Stich et al, 1975;McCann et al, 1976;Huberman and Sachs, 1976;Trosko and Hart, 1976;Abbondandolo, 1977;Brusick, 1977).…”

Section: Mutagenesismentioning

confidence: 99%

DNA REPAIR AND MUTAGENESIS IN MAMMALIAN CELLS*^,†

Hart

Hall

Daniel

1978

Photochem & Photobiology

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Mutations may result from imperfect DNA replication, unrepaired DNA damage, and errorprone DNA repair. DNA damage may induce any or all of these effects. Numerous physical and chemical agents damage DNA, and the repair of such damage may be either incomplete, error-free, or error-prone. It is assumed that correctly repaired DNA damage has no deleterious biological consequence. Unrepaired or misrepaired DNA damage has been related to such physiological changes as cell death, division suppression, gene repression and derepression, altered transcription, elevated CAMP levels, predisposition of the cell to viral transformation, decreased cellular respiration, and mutation. Defective DNA repair has been linked in man to cancer, birth defects, arteriosclerosis, high blood pressure, aging, and neurological dysfunction. Various clinical syndromes including xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Fanconi's anemia (FA), progeria, actinic keratosis (AK), and possibly Cockayne syndrome (CS) have been described as being defective in at least one of the various forms of DNA repair.There are at least four general types of enzymatic repair systems in mammalian cells (excision, strand break, postreplication, and photoreactivation). Each of these, except the latter, is composed of multiple pathways. The two most intensely studied of these repair systems are excision and postreplication repair.Excision repair presumably involves the error-free removal of damaged DNA by a complex of enzymes. The damaged segment is removed and replaced with newly synthesized DNA using the opposite strand as the template. A measure of excision repair may be made by assaying: (1) removal of known products; (2) production of single-strand breaks following treatment of cellular DNA with damage-specific endonuclease preparations; or (3) measurement of repair synthesis. Since (XP) individuals who are defective in the excision of ultraviolet (UV) light induced lesions are also defective in the repair of certain forms of chemically-induced DNA damage, and since the size of repaired regions for both acetoxy-acetylaminofluorene (AAAF) and UV-induced DNA damage were believed to be similar, it was assumed that similar mechanisms for the repair of both physically and chemicallyinduced DNA damage existed. Recent evidence, however, suggests that significant differences may exist in the repair of DNA damage induced by agents producing similar patch sizes. Excision repair capacity also appears to vary as a function of species, organ, state of differentiation, and pattern of chromatin association with DNA. Although there appear to be several enzymes specific for the recognition of specific forms of DNA damage, once recognition (nicking) has occurred, the subsequent sequence of events for most types of excision repair are presumed to be similar.Postreplication repair, which presumably may be either error-free or error-prone, is a process in which DNA, newly-synthesized from a defective or damaged template, is repaired. Postreplication repair is usually ...

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Metabolic Interactions Among Environmental Chemicals and Drugs

Cited by 245 publications

References 176 publications

Changes in lipid profiles of liver microsomes of rats following intratracheal administration of DDT or endosulfan

Changes in lipid profiles of liver microsomes of rats following intratracheal administration of DDT or endosulfan

Interactions between nutritional factors and drug biotransformations in man.

DNA REPAIR AND MUTAGENESIS IN MAMMALIAN CELLS*^,†

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Metabolic Interactions Among Environmental Chemicals and Drugs

Cited by 245 publications

References 176 publications

Changes in lipid profiles of liver microsomes of rats following intratracheal administration of DDT or endosulfan

Changes in lipid profiles of liver microsomes of rats following intratracheal administration of DDT or endosulfan

Interactions between nutritional factors and drug biotransformations in man.

DNA REPAIR AND MUTAGENESIS IN MAMMALIAN CELLS*,†

Contact Info

Product

Resources

About

DNA REPAIR AND MUTAGENESIS IN MAMMALIAN CELLS*^,†