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A H Conney

Publications and source records attributed to A H Conney.

At least 127 records · Page 7Linked to original sources
PubMed1983

Studies on the mutagenic activity of ascorbic acid in vitro and in vivo.

In vitro data are presented to show that ascorbic acid does not have intrinsic mutagenicity towards strain TA100 of S. typhimurium if deionized water is used to prepare the incubation medium. The addition of Cu2+ ions to the bacterial medium that contains ascorbic acid, or the use of tap water and ascorbic acid alone, causes a mutagenic and cytotoxic response that is blocked by EDTA. Additional in vitro data demonstrate that hydrogen peroxide is mutagenic to S. typhimurium strain TA100 and it is suggested that ascorbic acid may be mutagenic and cytotoxic through the generation of hydrogen peroxide. In vivo studies using a sensitive intrahepatic host-mediated mutagenicity assay indicate that ascorbic acid is not genotoxic in guinea pigs even when the dietary intake of vitamin C is above the level required for tissue saturation (5000 mg/kg body weight/day).

Animals↗
PubMed1983

The effect of steric strain in the bay-region of polycyclic aromatic hydrocarbons: tumorigenicity of alkyl-substituted benz[a]anthracenes.

3,6-Dimethylcholanthrene (3,6-DMC) and 7,11,12-trimethylbenz[a]anthrene (7,11,12-TMBA) were tested for tumor-initiating activity on mouse skin as an approach to evaluate the potential role of steric strain in the bay-region on tumorigenic potency. Methyl-substitution at the 6-position of 3-methylcholanthrene (3-MC) increases steric strain in the bay-region of the hydrocarbon as it does at the 12-position of benz[a]anthracene (BA) causing both hydrocarbons to become non-planar. 3,6-DMC had at least 2- to 3-fold higher tumor-initiating activity than did 3-MC. Introduction of an 11-methyl group in 7,12-dimethylbenz[a]anthracene (7,12-DMBA) results in the formation of a more highly hindered (buttressing effect) hydrocarbon. 7,11,12-TMBA had 5% or less of the tumor-initiating activity of 7,12-DMBA, although the hydrocarbon still had relatively high tumorigenic activity on mouse skin. The results obtained with 3,6-DMC and studies reported previously with other methyl-substituted hydrocarbons, show that hydrocarbons possessing steric strain in the bay-region of the molecule can have enhanced tumorigenic activity. The basis of this steric effect remains unclear, however, as a result of the decreased tumorigenic activity of the 11-methyl-substituted derivative of 7,12-DMBA. The weak tumor-initiating activity of BA was enhanced at least 4- to 8-fold as a result of methyl-substitution at the 6- and 8-positions (6,8-dimethylbenz[a]anthracene). The higher tumorigenic activity of 6,8-dimethylbenz[a]anthracene compared to BA is consistent with a presumed decrease in metabolic detoxification of the dimethyl-substituted derivative at the 5,6- and 8,9-double bonds.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Acetaminophen metabolism in subjects fed charcoal-broiled beef.

The effects of consumption of charcoal-broiled beef on the metabolism of acetaminophen by conjugation were determined in nine normal subjects. We had reported that beef prepared in this manner accelerates the oxidative metabolism of drugs, including the oxidation of phenacetin to N-acetyl-p-aminophenol (acetaminophen). In nine normal subjects, a control diet was followed by a charcoal-broiled beef diet, which was followed by the control diet. The charcoal-broiled beef had little or no effect on the plasma-level profile of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate, or on the urinary excretion of acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, 3-methoxy-acetaminophen, or the cysteine and mercapturic acid conjugates of acetaminophen. Results indicate that the enzyme systems that conjugate acetaminophen in man are subject to little or no influence by charcoal-broiled beef. Therefore dietary factors that increase drug oxidations cannot be assumed to have a similar effect on drug conjugation.

Acetaminophen↗
PubMed1983

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The delta 4-5 alpha-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diets is not known. Similar changes in steroid delta 4-5 alpha-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Inhibition of the mutagenicity of bay-region diol-epoxides of polycyclic aromatic hydrocarbons by phenolic plant flavonoids.

Myricetin, robinetin and luteolin inhibited the mutagenic activity resulting from the metabolic activation of benzo[a]-pyrene and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene by rat liver microsomes. These naturally occurring plant flavonoids and seventeen additional flavonoids and related derivatives with phenolic hydroxyl groups inhibited the mutagenic activity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), which is an ultimate mutagenic and carcinogenic metabolite of benzo[a]pyrene. Several flavonoids without phenolic hydroxyl groups or with methylated phenolic hydroxyl groups were inactive. The mutagenic activity of 0.05 nmol of BP 7,8-diol-9,10-epoxide-2 towards strain TA 100 of S. typhimurium was inhibited 50% by incubation of the bacteria and the diol-epoxide with myricetin (2 nmol), robinetin (2.5 nmol), luteolin (5 nmol), quercetin (5 nmol), 7-methoxyquercetin (5 nmol), rutin (5 nmol), quercetin (5 nmol), delphinidin chloride (5 nmol), morin (10 nmol), myricitrin (10 nmol), kaempferol (10 nmol), diosmetin (10 nmol), fisetin (10 nmol), or apigenin (10 nmol). Considerably less antimutagenic activity was observed for dihydroquercetin, naringenin, robinin, D-catechin, genistein, kaempferide and chrysin. Pentamethoxyquercetin, tangeretin, nobiletin, 7,8-benzoflavone, 5,6-benzoflavone, and flavone, which lack free phenolic groups, were inactive. The antimutagenic activity of hydroxylated flavonoids results from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2 since the rate of disappearance of the diol-epoxide from cell-free solutions in 1:9 dioxane:water was markedly stimulated by myricetin, robinetin and quercetin. Myricetin was a highly potent inhibitor of the mutagenic activity of bay-region diol-epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene and dibenzo[a,i]pyrene, but higher concentrations of myricetin were needed to inhibit the mutagenicity of the chemically less reactive benzo[a]pyrene 4,5-oxide and bay region diol-epoxides of benz[a]anthracene, chrysene and benzo[c]phenanthrene.

Animals↗
PubMed1983

Fluorine substitution as a probe for the role of the 6-position of benzo[a]pyrene in carcinogenesis.

The tumorigenic activities of benzo[a]pyrene (BP) and 6-fluorobenzo[a]pyrene (6-F-BP) were compared to determine whether an unsubstituted 6-position is important for the carcinogenic effect of BP. Highly purified samples of 6-F-BP and BP had similar activities for the induction of lung adenomas in Swiss Webster mice treated before weaning. The 6-fluoro derivative, however, had about one-half as much activity as BP for the initiation of skin papillomas in CD-1 mice. Similarly, 6-F-BP (approximately equal to 90% purity) had about one-half the activity of BP for the induction of skin tumors in C57BL/6J mice given repetitive treatments of the hydrocarbons and for the induction of sarcomas in C3H/fCum mice given a single sc injection. 6-F-BP (approximately equal to 90% purity) had activity similar to that of BP for induction of sarcomas at the sc injection site in Fischer 344 rats. These results and related data indicate the need for detailed metabolic studies whenever fluorine substitution is used as a probe to assess the role of the unsubstituted position in the carcinogenicity of the parent compound.

Animals↗
PubMed1983

Mutagenicity of the enantiomers of the diastereomeric bay-region benz(a)anthracene 3,4-diol-1,2-epoxides in bacterial and mammalian cells.

Enantiomers of the diastereomeric pair of bay-region benz(a)anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity in two histidine-dependent strains of Salmonella typhimurium, as well as in an 8-azaguanine-sensitive Chinese hamster cell line. In strain TA 98 of S. typhimurium, the diol-epoxide with (1S,2R,3R,4S) absolute configuration [(-)-diol-epoxide 2] was the most active isomer, although there was less than a 3-fold difference in the mutagenicity of the four diol-epoxides. However, in strain TA 100 of S. typhimurium, the enantiomeric diol-epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol-epoxide 2] was the most active diol-epoxide, and the two isomers with (3S,4R) absolute configuration [(-)-diol-epoxide 1 and (+)-diol-epoxide 2] were three to eight times more active than were the two isomers with (3R,4S) configuration. The highest degree of sensitivity to absolute configuration was observed in Chinese hamster V79 cells, in which the (1R,2S,3S,4R) isomer [(+)-diol-epoxide 2] was from three to 20 times more mutagenic than were the other three isomers. This metabolically predominant (+)-diol-epoxide 2 isomer, which has high activity in strain TA 100 of S. typhimurium and the Chinese hamster V79 cells, has the same absolute configuration as do the bay-region diol-epoxide isomers of benzo(a)pyrene and chrysene that have been shown previously to be exceptionally mutagenic to mammalian cells and highly tumorigenic in mice. Analysis of the mutagenic activity of the (+)- and (-)-isomers of the 1,2- and 3,4-tetrahydroepoxides of benz(a)anthracene revealed only small enantiomeric differences in strain TA 98 of S. typhimurium (2.5 fold) and little, if any, differences (less than 1.5-fold) in the other two mutagenicity systems. However, the extent to which the four tetrahydroepoxides were converted to nonmutagenic products by homogeneous microsomal epoxide hydrolase (EC 3.3.2.3) indicated marked differences in the stereoselectivity of the enzyme. (-)-(3R,4S)-Epoxy-1,2,3,4-tetrahydrobenz(a)anthracene appears to be an exceptionally good substrate for epoxide hydrolase.

Animals↗
PubMed1983

Betamethasone-mediated activation of biphenyl 2-hydroxylation in rat liver microsomes. Studies on possible mechanisms.

The addition of the steroid betamethasone to intact or detergent-solubilized rat liver microsomes caused a concentration-dependent increase in the rate of biphenyl 2-hydroxylation. Betamethasone (100 microM) increased the apparent Vmax for 2-hydroxybiphenyl formation 2- to 4-fold but had no effect on the apparent Km when either the biphenyl or NADPH concentration was varied. Betamethasone had little or no effect on the apparent Vmax or apparent Km of the 3- and 4-hydroxylations of biphenyl. The steroid did not enhance biphenyl 2-hydroxylation through a peroxidative mechanism. Betamethasone had little or no effect on the rate of the NADPH-dependent reduction of cytochrome c or total microsomal cytochrome P-450. The addition of purified NADPH-cytochrome P-450 reductase to cholate-solubilized liver microsomes increased the rate of hydroxylation of biphenyl in positions 2 and 4. Betamethasone (100 microM) decreased the apparent Km for purified cytochrome P-450 reductase by 48% and increased the apparent Vmax of 2-hydroxybiphenyl formation by 2-fold when the concentration of cytochrome P-450 reductase was varied. The steroid did not alter the Km or Vmax values for the 4-hydroxylation of biphenyl. The data suggest that betamethasone enhances the interaction between the reductase and the form(s) of cytochrome P-450 responsible for the 2-hydroxylation of biphenyl.

Animals↗
PubMed1983

Tumor-initiating activity of benz[c]acridine and twelve of its derivatives on mouse skin.

Benz[c]acridine (B[c]ACR) and 12 of its derivatives, including the 5 metabolically possible trans-dihydrodiols, the diastereomeric bay-region diol-epoxides, 2 non-bay-region diol-epoxides, and the K-region arene oxide, were tested for tumor-initiating activity on mouse skin. A single topical application of 0.4 to 2.5 mumol of compound was followed 12 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. B[c]ACR was a weak tumor initiator on mouse skin, producing a 37% tumor incidence and 1.33 tumors/mouse at the 2.5-mumol dose. Of the five metabolically possible trans-dihydrodiols of B[c]ACR, only trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR had significant tumor-initiating activity. This compound was at least 6-fold more active than was the parent compound at the three doses tested. The diastereomeric bay-region diol-epoxides, in which the epoxide oxygen is either cis(isomer 1) or trans (isomer 2) to the benzylic hydroxyl group, each had significant tumor-initiating activity, although isomer 2 was at least 5-fold more active than was isomer 1 and had activity equal to that of its potential metabolic precursor, trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR. Two non-bay-region diol-epoxides (isomer 2 of the 8,9-diol-10,11-epoxide and the 10,11-diol-8,9-epoxide) and the 5,6-arene oxide (K-region) were inactive at the doses tested. 3,4-Dihydro-B[c]ACR, the potential metabolic precursor of a bay-region tetrahydroepoxide, was the most potent tumor initiator analyzed in the present study. At an initiating dose of 0.4 mumol, this compound produced a 97% tumor incidence and 7.90 tumors/mouse after 15 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. These results suggest that B[c]ACR, the N-12 analogue of benz[a]anthracene, undergoes metabolic activation to an ultimate carcinogenic metabolite via formation of a bay-region diol-epoxide, as has already been demonstrated for benz[a]anthracene.

Acridines↗
PubMed1982

In vivo activation of zoxazolamine metabolism by flavone.

The metabolism of zoxazolamine to 6-hydroxyzoxazolamine by liver microsomes from neonatal rats is stimulated severalfold by the in vitro addition of flavone, a naturally occurring compound found in several plant species. The intraperitoneal injection of flavone into neonatal rats causes an immediate several-fold stimulation in the rate of total body metabolism of simultaneously administered zoxazolamine. This is the first demonstration of stimulation of oxidative drug metabolism in vivo by a zenobiotic that is an activator of hepatic microsomal.

Animals↗
PubMed1982

Absence of seasonal variation in antipyrine metabolism.

The induced activity of aryl hydrocarbon hydroxylase (AHH), measured by the metabolism of benzo[a]pyrene to fluorescent products in cultured human lymphocytes, shows a strong seasonal variation. The in vivo metabolism of antipyrine, which is also catalyzed by microsomal cytochrome P-450-dependent monooxygenases, has been reported to be correlated with AHH inducibility in human lymphocytes. To determine whether antipyrine metabolism also showed seasonal changes, we measured antipyrine half-life (t 1/2) in 10 nonsmokers and eight smokers at the two times of the year that correspond to the high and low peaks of inducible AHH activity as measured in lymphocytes. The mean antipyrine t 1/2 determined in all 18 subjects in summer was almost identical to that found in winter (mean +/- SEM = 10.90 +/- 0.65 and 10.96 +/- 0.78 hr). AHH activity in cultured human lymphocytes from the nonsmoking subjects was determined in control and 3-methylcholanthrene-induced cells to obtained inducibility ratios of 4.2 +/- 0.56 (SEM) in the summer and 1.4 +/- 0.14 (SEM) in winter. These results indicate that the seasonal variation in AHH inducibility in human lymphocytes is not reflected by a corresponding seasonal variation in antipyrine metabolism in vivo.

Adult↗
PubMed1982

Cigarette smoking and chlorpromazine disposition and actions.

Chlorpromazine, 75 mg, was taken by eight cigarette smokers and nine nonsmokers. Mean maximum percent decrease in mean blood pressure with change in position from lying to standing during the first 10 hr after chlorpromazine was 46% greater in nonsmokers than in smokers. Of the eight smokers, six did not become sleepy after chlorpromazine, one became slightly sleepy, and one fell asleep. Of the nine nonsmokers, three became slightly sleepy, one moderately sleepy, and five fell asleep. Mean peak plasma concentration of chlorpromazine was 24% lower and mean area under the plasma concentration-time curve (AUC) was 36% lower in smokers than in nonsmokers. There was no correlation between these plasma level parameters and either the degree of sleepiness or the degree of orthostatic hypotension in the subjects. The relatively small differences between cigarette smokers and nonsmokers in AUCs and peak plasma levels for chlorpromazine, combined with the lack of relationship between these plasma level parameters, the occurrence of drowsiness, and the magnitude of orthostatic hypotension in our subjects make it unlikely that cigarette smoking influenced these effects of chlorpromazine by enhancing its overall metabolism.

Adult↗
PubMed1982

Mechanism of the inhibition of mutagenicity of a benzo[a]pyrene 7,8-diol 9,10-epoxide by riboflavin 5'-phosphate.

Riboflavin 5'-phosphate (flavin mononucleotide; FMN) inhibits the mutagenicity of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P diol epoxide), the only known ultimate carcinogenic metabolite of benzo[a]pyrene. Coincubation of 10, 25, and 50 nmol of FMN with strain TA100 of histidine-dependent Salmonella typhimurium inhibits the mutagenicity of 0.05 nmol of the diol epoxide by 50, 70, and 90%, respectively. Ribose 5-phosphate and riboflavin show no significant effects at comparable doses. Reaction of B[a]P diol epoxide with FMN in aqueous solution at neutral pH produces only tetraols, with no evidence for covalent adducts. At pH 7 the rate of hydrolysis of B[a]P diol epoxide in dioxane/water, 1:9 (vol/vol), at 25 degrees C is increased more than 10-fold in the presence of 100 muM FMN. Spectrophotometric studies and quantitative rate data for the reaction of the diol epoxide with FMN indicate that a complex is formed between the diol epoxide and the flavin moiety of FMN (Ke = 1,400-3,400 M-1) prior to general acid-catalyzed hydrolysis of the epoxide to tetraols by the phosphate monoanion of FMN. Comparable concentrations of ribose 5-phosphate and riboflavin do not significantly increase the rate of hydrolysis, although evidence for complex formation between riboflavin and the diol epoxide is observed. General acid-catalyzed hydrolysis of bay-region polycyclic hydrocarbon diol epoxides by compounds that have a high affinity for these ultimate carcinogens represents a potentially useful way of inhibiting their carcinogenic activity.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗