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Biomedical subjects

R Kuntzman

Publications and source records attributed to R Kuntzman.

At least 19 recordsLinked to original sources
PubMed1979

Stimulatory effect of phenobarbital on the metabolism of the oral contraceptive 17 alpha-ethynylestradiol-3-methyl ether (mestranol) by rat liver microsomes.

Pretreatment of rats with phenobarbital for 4 days stimulates the activity of liver microsomal enzymes that metabolize 17 alpha-ethynylestradiol-3-methyl ether (mestranol). This effect provides an explanation for the decreased uterotropic action of mestranol in rats pretreated with phenobarbital and may provide an explanation for unwanted pregnancies in women taking oral contraceptives in combination with phenobarbital or other enzyme-inducing drugs.

Animals↗
PubMed1977

Inhibition by CO of hepatic benzo[a]pyrene hydroxylation and its reversal by monochromatic light.

Inhibition by CO of benzo[a]pyrene hydroxylation was studied in hepatic microsomes from rats pretreated with phenobarbital, 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin, from animals treated with vehicle (saline or corn oil, respectively), and in a reconstituted microsomal cytochrome P-448 system prepared from rats treated with 3-methylcholanthrene. In all preparations the hydroxylation was inhibited by CO, and this inhibition was most effectively reversed by irradiation with monochromatic light of 450 nm wavelength. These observations provide direct evidence that the oxygen-activating component of all the examined benzo[a]pyrene hydroxylase systems is a P-450-type heme protein. The only striking difference observed in these systems was the low CO sensitivity of the benzo[a]pyrene hydroxylase reaction in microsomes from animals treated with 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Half-maximal inhibition occurred at CO/O2 ratios of 9--12, rather than at 1--2, which is the usual range for P-450-linked mixed-function oxidase reactions. In contrast, the reconstituted benzo[a]pyrene hydroxylase system, with purified cytochrome P-448 from 3-methylcholanthrene-induced rats, exhibited a considerably higher sensitivity towards CO (CO/O2 ratio approximately 1), well within the range for mixed-function oxidase reactions. It is concluded that the observed diminished CO sensitivity of microsomal benzo[a]pyrene hydroxylase in 3-methylcholanthrene- or 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats results from alterations in the composition and/or structural organization of the microenvironment of cytochrome P-448 in the endoplasmic reticulum in response to the inducing action of polycyclic aromatic hydrocarbons and related agents, and is not related to changes in the heme protein P-448 per se. The detailed nature of these changes is the subject of ongoing studies.

Animals↗
PubMed1977

Phenacetin metabolism: effect of hydrocarbons and cigarette smoking.

The effects of cigarette smoking on phenacetin metabolism in the rat and in man have been investigated. Exposure of rats to cigarette smoke or pretreatment with the polycyclic hydrocarbon, 3,4-benzpyrene (benzo[a]pyrene), resulted in a more rapid disappearance of phenacetin in vivo. Additional studies demonstrated that hydrocarbon and smoking pretreatment of rats enhanced the 0-dealkylation of phenacetin to N-acetyl-p-aminophenol (APAP) by the intestinal mucosa. Cigarette smoking also increased the metabolism of phenacetin in man. The plasma concentration of phenacetin in cigarette smokers was lower than that in nonsmokers, whereas the ratio of the concentration of APAP to that of phenacetin was increased severalfold in the smokers. No difference in plasma half-life of elimination of phenacetin or in the amount of APAP excreted was found between smokers and nonsmokers. The lower blood levels of phenacetin in cigarette smokers could be the result of increased intestinal metabolism of the drug and/or first-pass metabolism in the liver.

Animals↗
PubMed1977

Regulation of drug metabolism in man by environmental chemicals and diet.

Studies in animals have shown that many environmental pollutants induce the synthesis or inhibit the activity of microsomal mixed-function oxygenases that metabolize drugs, carcinogens and normal body constituents such as steroid hormones. These effects on microsomal enzyme activity alter the duration and intensity of action of foreign and endogenous chemicals in animals, and such effects on metabolism may influence the carcinogenicity of some pollutants in man. Studies on the effects of environmental chemicals on drug metabolism in man are sparse. Exposure of humans to DDT or lindane in a pesticide factory results in an enhanced rate of metabolism of antipyrine and phenylbutazone and an increased urinary excretion of 6-beta-hydroxycortisol. Polycyclic aromatic hydrocarbons present in cigarette smoke, in charcoal-broiled meats, and in polluted city air are potent inducers of drug-metabolizing enzymes in animals. In humans, cigarette smoking stimulates the activity of placental enzymes that metabolize several drugs and carcinogens. In addition, cigarette smokers metabolize phenacetin, theophylline, and other drugs more rapidly in vivo than nonsmokers. Dietary factors are important in the regulation of drug metabolism in animals and man. Feeding rats brussels sprouts or cabbage stimulates the intestinal and hepatic metabolism of drugs in animals. This effect is caused, at least in part, by certain indoles normally present in these vegetables. The feeding of a charcoal-broiled beef diet to rats stimulates the metabolism of phenacetin in vitro, and a similar diet stimulates the in vivo metabolism of phenacetin in man. It is likely that polycyclic aromatic hydrocarbons are the major inducers in charcoal-broiled beef.

Animals↗
PubMed1976

Stimulatory effect of vegetables on intestinal drug metabolism in the rat.

The intestinal metabolism of hexobarbital, phenacetin, 7-ethoxycoumarin and benzo [a] pyrene in vitro was increased in rats fed either dried Brussels sprouts or dried cabbage in a nutritionally complete semisynthetic diet as compared to rats fed only the semisynthetic diet. Pretreatment of rats with several indoles present in Brussels sprouts and cabbage also stimulated intestinal drug metabolism, but the effect was smaller than when dried Brussels sprouts or dried cabbage was fed. The results obtained suggest a need for studies in man to determine whether vegetables and other dietary constituents can stimulate the intestinal metabolism of drugs and thereby alter their biological effects.

Animals↗
PubMed1975

Intestinal metabolism of phenacetin in the rat: effect of charcoal-broiled beef and rat chow.

The intestinal metabolism of phenacetin in vitro was increased 1100 percent in rats fed charcoal-broiled ground beef in a semisynthetic diet. The intestinal metabolism of phenacetin was increased 200 percent in rats fed a chow diet, as compared to rats fed the semisynthetic diet. The results obtained suggest a need for studies in man to determine whether charcoal-broiled meat and other dietary constituents can stimulate the intestinal metabolism of phenacetin or other drugs and thereby decrease their absorption and bioavailability.

Animals↗
PubMed1975

Partial purification and separation of multiple forms of cytochrome. P-450 and cytochrome P-448 from rat liver microsomes.

1. Partial purification of liver microsomal cytochrome p-450 results in the separation of two forms of cytochrome p-450 from phenobarbital-treated rats and two forms of cytochrome p-44, from 3-methylcholanthrene-treated rats. 2. Each of the four cytochrome fractions had different spectral properties (absolute spectra, CO differences spectra, and ethylisocyanide difference spectra). 3. The hemeprotein in fractions which elute from a DEAE-cellulose column at 100 mKM KCl fraction IV B) are more highly purified than the hemeproteins (fraction IV A) that elute in the column volume. 4. The more highly purified cytochrome fractions (IV B) contain 9-11 moles of cytochrome P-450 or P-448 per mg protein (an approximately 5-7 fold purification over microsomes) and are enzymatically active in the metabolism of a variety of substrates when combined with lipid and NADPH-cytochrome c reductase. These hemeprotein fractions are free of cytochrome b5 and NADPH-cytochrome c reductase, and the hemeproteins are purified approximately 100-fold with respect to phospholipid. The cytochrome P-450 and P-448 are virtually free of epoxide hydrase.

Animals↗
PubMed1975

Inhibition of the acute toxicity and adrenocorticolytic effect of 7,12-dimethylbenz(a)anthracene by isopropylvaleramide and allylisopropylacetamide in the rat.

Isopropylvaleramide (IVA) and allylisopropylacetamide (AIA) inhibit hemorrhagic adrenocortical necrosis and mortality caused by 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats. Unlike their effect on hepatic microsomal cytochrome P-450, the anti-DMBA action of these compounds does not depend on the presence of the reactive allyl group in the molecule. Similarly, related barbiturates, regardless of whether they contain, like AIA, an allyl group and consequently destroy cytochrome P-450 (secobarbital and aprobarbital) or have, like IVA, saturated side chains and therefore do not effect the microsomal hemoprotein (pentobarbital and phenobarbital), proved ineffective in preventing both adrenal damage and death caused by DMBA. Hence, the protective action of IVA and AIA cannot be attributed to the destruction of the microsomal enzyme system responsible for the activation of DMBA. The toxicity of another carcinogen, dimethylnitrosamine, which also requires metabolic activation by microsomal enzymes, is not influenced by either IVA or AIA. IVA, which counteracts the adrenocorticolytic action of DMBA when given prior to, simultaneously with, or even after this carcinogen, has no discernible effect on hydrocarbon metabolism in vivo or in vitro. IVA is one of the most powerful inhibitors of the acute toxicity of DMBA. It has the simplest aliphatic structure and the smallest molecule among protectors of the adrenals against hydrocarbon-induced damage; its mechanism of action awaits further elucidation.

9,10-Dimethyl-1,2-benzanthracene↗