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Biomedical subjects

A H Conney

Publications and source records attributed to A H Conney.

At least 199 records · Page 11Linked to original sources
PubMed1978

Exceptional carcinogenic activity of benz[a]anthracene 3,4-dihydrodiol in the newborn mouse and the bay region theory.

Benz[a]anthracene and the five metabolically possible trans-dihydrodiols of benz[a]anthracene were tested for carcinogenicity in newborn Swiss-Webster mice. Four hundred, 800, and 1600 nmoles hydrocarbon i.p. were sequentially injected on Days 1, 8, and 15 of life. The mice were killed at 22 weeks of age. Of the mice treated with trans-3,4-dihydroxy-3, 4-dihydrobenz[a]anthracene, 24% developed malignant lymphoma, whereas 4% of the animals treated with benz[a]anthracene had malignant lymphoma. None of the animals treated with the trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene, trans-5,6-dihydroxy-5,6-dihydrobenz[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenz[a]anthracene, or trans-10,11-dihydroxy-10,11-dihydrobenz[a]anthracene had malignant lymphoma. trans-3,4-Dihydroxy-3,4-dihydrobenz[a]anthracene caused about 35-fold more pulmonary adenomas than did benz[a]anthracene, whereas the trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene, trans-5,6-dihydroxy-5,6-dihydrobenz[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenz[a]anthracene, and trans-10, 11-dihydroxy-10,11-dihydrobenz[a]anthracene had little or no activity. The exceptionally high carcinogenicity of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene is consistent with the metabolism of this compound to either or both of the diastereomeric bay region 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracenes, and the data support the bay region theory of polycyclic hydrocarbon carcinogenesis.

Adenoma↗
PubMed1978

Evidence for bay region activation of chrysene 1,2-dihydrodiol to an ultimate carcinogen.

The tumor-initiating activities of chrysene and the three metabolically possible trans-dihydrodiols at the 1,2-, 3,4-, and 5,6-positions of chyrsene were determined on the skin of female CD-1 mice. A single topical application of 0.4, 1.25, or 4.0 mumol of each compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. The most potent tumor initiator was chrysene 1,2-dihydrodiol, which had approximately twice the tumorigenic activity of the parent hydrocarbon chrysene at all doses tested. Chrysene 3,4-dihydrodiol and chrysene 5,6-dihydrodiol had no significant tumorigenic activity. 1,2-Dihydroxy-1,2,3,4-tetrahydrochrysene, a compound related to chrysene 1,2-dihydrodiol but with the conjugated nonaromatic double bond removed from the 3,4-position of the molecule, had less than 25% of the tumorigenic activity of chrysene 1,2-dihydrodiol. These results indicate that chrysene 1,2-dihydrodiol is a proximate carcinogenic metabolite of chrysene and that a chrysene 1,2-diol-3,4-epoxide, in which the epoxide group forms part of the bay region in the molecule, is a likely candidate as an ultimate carcinogenic metabolite of chrysene.

Animals↗
PubMed1978

Marked differences in the carcinogenic activity of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in newborn mice.

Optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrenes [(+)- and (-)-BP 7,8-dihydrodiol] were tested for carcinogenicity by giving newborn mice i.p. injections of 20, 40, and 80 nmol of compound on Days 1, 8, and 15 of life. The animals were killed at 17 weeks of age. Control mice had 0.10 pulmonary adenoma per mouse, whereas animals treated with (+)-BP 7,8-dihydrodiol and (-)-BP 7,8-dihydrodiol had 0.16 and 9.28 pulmonary adenomas per mouse, respectively. When a 5-fold higher dose was administered according to the above dosage schedule, (+)-dihydrodiol caused 2.34 pulmonary adenomas per mouse and (-)-BP 7,8-dihydrodiol caused 32.2 pulmonary adenomas per mouse. When 200, 400, and 800 nmol of benzo(a)pyrene or (+)-BP 7,8-dihydrodiol were administered sequentially on Days 1, 8, and 15 of life, 4.13 and 18.5 pulmonary adenomas per mouse, respectively, were observed when the mice were 17 weeks of age. This high dose of (-)-BP 7,8-dihydrodiol killed most of the mice. Administration of (-)-BP 7,8-dihydrodiol caused a high incidence of malignant lymphomas, whereas (+)-BP 7,8-dihydrodiol and benzo(a)pyrene had little or no ability to cause malignant lymphomas.

Adenoma↗
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

Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes.

The comparative hydration of styrene 7,8-oxide, octene 1,2-oxide, naphthalene 1,2-oxide, phenanthrene 9,10-oxide, benzo[a]anthracene 5,6-oxide, 3-methylcholanthrene 11,12-oxide, dibenzo[a,h]anthracene 5,6-oxide, and benzo[a, 7,8-, 9,10-, and 11,12-oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10-oxide was the best substrate for the human and rat epoxide hydrases and dibenzo[a,h]anthracene 5,6-oxide and benzo[a-a)pyrene 11, 12-oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydrase with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.

Alkenes↗
PubMed1977

Comparative metabolism of benzo[a]pyrene and drugs in human liver.

The oxidative metabolism of antipyrine, hexobarbital, coumarin, zoxazolamine, 7-ethoxycoumarin, and the chemical carcinogen benzo[a]pyrene (BP) was studied in 32 adult human livers obtained at autopsy. When enzyme activity for one substrate was plotted against enzyme activity for a second substrate for each of the 32 livers, statistically significant correlations were found between the rates of metabolism of BP and the rates of metabolism of each of the other five drug substrates. The degree of correlation was dependent upon the substrate pair that was studied. Highly significant statistical correlations (p less than 0.001) for monooxygenase activities among the different livers were observed for BP with antipyrine (r = 0.85), antipyrine with zoxazolamine (r = 0.82), antipyrine with hexobarbital (r = 0.79), zoxazolamine with 7-ethoxycoumarin (r = 0.75), antipyrine with coumarin ( r= 0.72), zoxazolamine with coumarin (r = 0.72), BP with hexobarbital (r = 0.72), hexobarbital with coumarin (r = 0.71), BP with zoxazolamine (r = 0.69), hexobarbital with zoxazolamine (r = 0.64), coumarin with 7-ethoxycoumarin (r = 0.61), and BP with coumarin (r = 0.57). Less significant correlations were obtained for BP with 7-ethoxycoumarin (r = 0.35; p = 0.05). It is not known whether the relationships between the metabolism of the several substrates described here for autopsy livers would also occur with fresh livers. The lack of a perfect correlation for any of the substrate pairs suggests the presence in human liver of multiple monooxygenase enzyme systems for the metabolism of benzo[a]pyrene and the five other substrates studied, as well as heterogeneity in their distribution among the 32 livers that were examined. The approach described in the present report may have significance in the study of the comparative metabolism of drugs, chemical carcinogens, and other environmental pollutants by human tissues and may help us find predictor drugs that will be useful for evaluating the drug- and carcinogen-metabolizing capacity of different individuals in the human population.

Adolescent↗
PubMed1977

Activation of monooxygenases in human liver by 7,8-benzoflavone.

Addition of 10(-4) M 7,8-benzoflavone to homogenates of human liver samples obtained by autopsy or surgical biopsy increased the rate of benzo[a]pyrene hydroxylation up to 11-fold. 7,8-Benzoflavone also increased the rates of hydroxylation of zoxazolamine and antipyrine at 10(-4) M but inhibited these reactions at 10(-6) M. The effects of 7,8-benzoflavone on the hydroxylation of benzo[a]pyrene and zoxazolamine in microsomes from human liver were similar to those in homogenates. Addition of 7,8-benzoflavone to homogenates of surgical biopsy samples of human liver had little or no effect on the rates of oxidative metabolism of 7-ethoxycoumarin, coumarin, and hexobarbital. Marked individuality for the activating and inhibiting effects of 7,8-benzoflavone was observed in different liver samples. This individuality may result both from the presence of multiple monooxygenases in varying amounts and proportions in the different liver samples and from a selective effect of 7,8-benzoflavone on certain of the monooxygenases.

Adolescent↗
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

Quantitative determination of phenacetin and its metabolite acetaminophen by GLC-chemical ionization mass spectrometry.

A quantitative GLC-mass spectrometric procedure was developed for the determination of phenacetin and its O-desethyl metabolite, acetaminophen, in human plasma. The assay utilizes selective ion detection to monitor, in a GLC effluent, the MH+ molecular ions of both phenacetin and the methyl derivative of acetaminophen, p-acetanisidine, generated by isobutane chemical ionization. Deuterated analogs of phenacetin and acetaminophen, phenacetin-d3 and acetaminophen-d3, respectively, are added to the plasma before extraction to serve as internal standards. To determine phenacetin and unconjugated acetaminophen, 1.0 ml of plasma is extracted with 5 ml of benzene-dichloroethane (7:3). The extraction solvent is removed, and the residue is methylated with diazomethane. Th solution is again evaporated to dryness, and the residue is reconstituted in ethyl acetate. A portion of this solution is then analyzed by GLC-mass spectrometry, with the mass spectrometer set to monitor m/e 166 (p-acetanisidine), 169 (p-acetanisidine-d3), 180 (phenacetin), and 183 (phenacetin-d3). To determine total acetaminophen, 0.1 ml of plasma is treated with a mixture of beta-glucuronidase and sulfatase, extracted with ethyl acetate, methylated, and analyzed by GLC-mass spectrometry. The procedure has a sensitivity limit of 1 ng of phenacetin/ml and 0.1 mug of acetaminophen/ml. The curves relating the amount of phenacetin and acetaminophen added versus the amount of phenacetin and acetaminophen found for 12 known phenacetin concentrations over the 9.9-246.6-ng/ml range and for 16 known acetaminophen concentrations over the 0.52-13.10-mug/ml range are straight lines with intercepts of nearly zero and with slopes of unity. Analyses of six separate plasma samples, each containing 25 ng of phenacetin/ml and 1.31 mug of acetaminophen/ml, had a precision of +/- ng/ml for phenacetin and +/- 0.08 mug/ml for acetaminophen.

Acetaminophen↗