Search PubMed⌕ Search

Biomedical subjects

A H Conney

Publications and source records attributed to A H Conney.

At least 235 records · Page 13Linked to original sources
PubMed1976

Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man.

This study was undertaken to examine the influence of changes in dietary carbohydrate and protein content on the oxidation of antipyrine and theophylline in man. When the diets of 6 normal volunteers were changed from their usual home diets to low carbohydrate-high protein diets, the plasma half-life of antipyrine decreased from 16.2 hr to 9.5 hr, and the half-life of theophylline decreased from 8.1 hr to 5.2 hr. When the subjects' diets were changed from low carbohydrate-high protein diets to a high carbohydrate-low protein diets, the mean antipyrine half-life increased from 9.5 hr to 15.6 hr and the mean theophylline half-life increased from 5.2 hr to 7.6 hr. These changes in half-lives were accompanied by changes in metabolic clearance rates but not in the apparent volumes of distribution of the drugs tested. Qualitatively similar results were obtained when the subjects were placed on standard diets followed by the standard diets supplemented with carbohydrate or protein. Supplementing the standard diets with carbohydrate caused an increase in drug half-lives, whereas a protein supplement caused a decrease in the drug half-lives. These data demonstrate marked influences of nutritional factors on oxidative biotransformation of drugs in man.

Adult↗
PubMed1976

Carcinogenicity of benzo[a]pyrene 4,5-, 7,8-, and 9,10-oxides on mouse skin.

Benzo[a]pyrene and three arene oxides of benzo[a]pyrene (benzo[a]pyrene 4,5-, 7,8-, and 9,10-oxides) have been tested for carcinogenicity in mice by topical application of each compound (0.1 or 0.4 mumol) once every 2 weeks for 60 weeks. At the high dose, benzo[a]pyrene and the 7,8-oxide were highly carcinogenic, whereas the 4,5-oxide (K-region oxide) was weakly active and the 9,10-oxide was inactive. At the low dose, only benzo[a]pyrene was highly carcinogenic. The carcinogenic activities of the three arene oxides of benzo[a]pyrene were not correlated with their stabilities or mutagenic activities.

Animals↗
PubMed1976

Metabolism of benzo[a]pyrene: conversion of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to highly mutagenic 7,8-diol-9,10-epoxides.

Metabolites of (+/-)-trans 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene formed by a rat liver microsomes and by a highly purified monoxygenase system were analyzed by high-pressure liquid chromatography. Four stereoisomeric tetraols of 7,8,9,10-tetrahydrobenzo[a]pyrene, known solvolysis products of the two highly mutagenic stereoisomers of the 9,10-epoxide of the 7,8-dihydrodiol, were identified as products. The ratio of the two highly unstable diol epoxides formed (7 beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, diol epoxide 1; 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, diol epoxide 2) ranged from about 1.7 to 0.4. The diol epoxides are sufficiently reactive to alkylate phosphate buffer (pH 7.4) at 37 degrees. Microsomes, particularly those from control animals, formed a substantial amount of an additional metabolite that appears to be phenolic. In analogy to benzo[a]pyrene, the metabolism of the 7,8-dihydrodiol shows similar induction after pretreatment of rats with phenobarbital or 3-methylcholanthrene. Neither diol epoxide appears to be a substrate for epoxide hydrase based on the ratis of tetraols formed in the presence or absence of epoxide hydrase. In view of the known carcinogenicity of benzo[a]pyrene 7,8-oxide and 7,8-dihydrodiol and of the marked mutagenicity of the stereoisomeric diol epoxides, both of these diol epoxides qualify for consideration as "ultimate carcinogen(s)" of benzo[a]pyrene.

Animals↗
PubMed1976

(+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo (a)pyrene: a potent skin carcinogen when applied topically to mice.

(+/-)-trans-7,8-Dihydroxy-7,8-dihydrobenzo[a]-pyrene, a known metabolite of benzo [a]pyrene, has been tested for carcinogenic activity on mouse skin by topical application of 0.15 or 0.30 mumol every 2 weeks for 60 weeks. At the low dose (0.15 mumol), the compound was equipotent to the parent hydrocarbon, benzo[a]pyrene, and considerably more potent than its metabolic precursor, benzo[a]pyrene 7,8-oxide, in eliciting tumors, as determined by both the onset of tumors and the total number of animals developing carcinomas. Application of 7,8-epoxy-,8,9,10-tetrahydrobenzo[a]pyrene (0.30 mumol every 2 weeks), a compound related to the carcinogenic benzo[a]pyrene 7,8-oxide but with the double bond removed from the 9,10-position of the molecule, did not elicit any tumors. The above results indicate that the (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene is a more proximate carcinogen than benzo[a]pyrene 7,8-oxide and that the carcinogenicity of benzo[a]pyrene 7,8-oxide and (+/-)trans-7,8-digydrobenzo[a]pyrene may be due to metabolic conversion of these compounds to the highly reactive and mutagenic stereoisomers of 7,8-digydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Animals↗
PubMed1976

Interactions between nutritional factors and drug biotransformations in man.

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 P-450 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 follwoing 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 hr 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.

Adult↗
PubMed1976

Mutagenicity and cytotoxicity of benzo(a)pyrene arene oxides, phenols, quinones, and dihydrodiols in bacterial and mammalian cells.

Twenty-nine benzo(a)pyrene derivatives were tested for mutagenic acitivity without metabolic activation in Salmonella typhimurium strains TA98, TA100, and TA1538 and in Chinese hamster V79 cells. The compounds studied included 4 arene oxides, all 12 isomeric phenols, 5 quinones, and 8 dihydrodiols. Benzo(a)pyrene 4,5-oxide was the most mutagenic of the compounds tested in both the bacterial and mammalian systems. The other arene oxides [benzo(a)pyrene 7,8-, 9,10-, and 11,12-oxides] were only weakly mutagenic in the S. typhimurium strains. However, in Chinese hamster V79 cells benzo(a)pyrene 11,12-oxide. Among the phenols, 6-hydroxybenzo(a)pyrene and 12-hydroxybenzo(a)pyrene were moderately mutagenic in strain TA98 of S. typhimurium, and 6-hydroxybenzo(a)pyrene was moderately mutagenic in V79 cells. The other 10 phenols, 5 quinones [benzo(a)pyrene 1,6-, 3,6-, 4,5-, 6, 12-, and 11,12-quinones] and 8 dihydrodiols [benzo(a)pyrene cis-4,5,trans-4,5-, cis-7,8-, trans-7,8-, cis-9,10-, trans-9,10-, cis-11,12-, and trans-11, 12-dihydrodiols] were eitherinactive or only weekly mutagenic. 1-Hydroxybenzo(a)pyrene and 3-hydroxybenzo(a)pyrene were weakly mutagenic in strain TA98 of S. typhimurium, and benzo(a)pyrene 7,8-dihydrodiol was weakly mutagenic in V79 cells. Benzo(a)pyrene 11,12-quinone was extremely cytotoxic to the V79 cells but had no observable toxicity in the bacterial strains.

Animals↗
PubMed1976

Mutagenicity and cytotoxicity of benzo(a)pyrene benzo-ring epoxides.

Four benzo-ring epoxides of the environmental carcinogen benzo(a)pyrene (BP) were tested for mutagenic and cytotoxic activity in 3 strains of Salmonella typhimurium (TA1538, TA98, and TA100) and in Chinese hamster V79 cells. Although very unstable in aqueous solution, 7beta,8alpha-dihydroxy-0beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol epoxide 1), with the 7-hydroxyl group on the same face of the molecule as the epoxide oxygen, was 1.5 to 4 times as mutagenic in the bacterial strains as was its more stable stereoisomer 7beta,8alpha-dihydroxy-9alpha,10beta-epoxy-7,8,9.10-tetrahydrobenzo(a)pyrene (diol epoxide 2). In V79 cells, diol epoxide 1 had one-third the mutagenic activity of diol epoxide 2 but was at least 10 times more labile than diol epoxide 2 in the tissue culture medium. The half-life of diol epoxide 1 in tissue culture medium was about 30 sec, whereas the half-life of diol epoxide 2 was between 6 and 12 min. 9,10-Epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, which is saturated in the benzo ring, is also very unstable and has mutagenic activity equal to or greater than diol epoxide 1 in the bacterial and mammalian cells. 7,8-Epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was more stable in aqueous solution than any of the 9,10-epoxides of BP but was much less mutagenic in both the bacterial and mammalian cells. In v79 cells, diol epoxides 1 and 2 and 9,10-opoxy-7,8,9,10-tetrahydrobenzo(a)pyrene were more than 40 times more cytotoxic than 7,8-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. The mutagenicity of the 2 tetrahydro epoxides toward strain TA98 of S. typhimurium was readily abolished by purified epoxide hydrase, whereas the mutagenic activity of the 2 diol epoxides was relatively unaffected by coincubation with the enzyme.

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↗
PubMed1976

Lack of carcinogenicity of 4-, 5-, 6-, 7-, 8-, 9-, and 10-hydroxybenzo(a)pyrene on mouse skin.

Seven phenols of benzo(a)pyrene (4-, 5-, 6-, 7-, 8-, 9-, and 10-hydroxybenzo(a)pyrene) were tested for carcinogenicity on mouse skin by application of 0.4 mumole of compound once every two weeks for 56 weeks. None of the seven phenols tested was carcinogenic to mouse skin, while treatment with the same dose of benzo(a)pyrene produced tumors in 92% of the treated animals. The lack of carcinogenicity of 7- and 8-hydroxybenzo(a)pyrene indicates that the strong carcinogenic activity previously reported for benzo(a)pyrene 7,8-oxide was not due to either phenolic isomerization product of this arene oxide.

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↗