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Biomedical subjects

C M King

Publications and source records attributed to C M King.

At least 145 records · Page 8Linked to original sources
PubMed1982

Rat mammary gland carcinogenesis after local injection of N-hydroxy-N-acyl-2-aminofluorenes: relationship to metabolic activation.

A single local injection of 2.5 mumol of N-hydroxy-N-formyl-2-aminofluorene (N-hydroxy-FAF), N-hydroxy-N-acetyl-2-aminofluorene (N-hydroxy-AAF), or N-hydroxy-N-pro-pionyl-2-aminofluorene )N-hydroxy-PAF) to each of the six left mammary glands of female Sprague-Dawley derived CD rats gave a mammary tumor incidence, after 12 months, of 53% for the N-acetyl (42% adenocarcinoma, 11% fibroadenoma), 41% for the N-formyl (8% adenocarcinoma, 11% sarcoma, 22% fibroadenoma), and 33% for the N-propionyl (11% adenocarcinoma, 22% fibroadenoma) derivatives of N-hydroxy-N-2-aminofluorene, Latent periods for malignant tumor appearance (adenocarcinoma or sarcoma) was 210 days, 148 days, and 177 days, respectively, with no malignant tumors occurring in the vehicle-treated animals. In contrast, latent periods for benign tumor appearance (fibroadenoma) was 263 days for control animals, 289 days for the N-hydroxy-AAF, 324 days for the N-hydroxy-FAF, and 317 days for the N-hydroxy-PAF animals. When N-acetyl-2-aminofluorene (AAF) was applied as above there was only an 8% mammary tumor incidence (4% adenocarcinoma, 4% fibroadenoma) with a latent period of 207 days for malignant tumor (adenocarcinoma) and 221 days for benign tumor (fibroadenoma) appearance. Arylhydroxamic acid N, O-acyltransferase activity has been demonstrated in the mammary glands of male, and lactating and non-lactating female Sprague-Dawley derived CD rats by means of nucleic acid binding assay. Mammary gland cytosol catalyzed tRNA adduct formation to a greater extent with N-hydroxy-FAF. AAF was not activated by this enzyme. Ammonium sulfate fractionation demonstrated the presence of two enzymes, one specific for N-hydroxy-FAF (70-80% fraction), the other specific for N-hydroxy-AAF and N-hydroxy-PAF (40-70% fraction). Moreover, gel filtration chromatography of mammary gland cytosol demonstrated the presence of two enzymes of differing acyl specificity. Mammary gland microsomes catalyzed the formation of tRNA adducts, but only with the N-hydroxy-FAF derivative. Assays that tested the mutagenic potential of the arylhydroxamic acids in Salmonella typhimurium TA-1538 with either mammary gland cytosol or microsomes demonstrated the order of mutagenicity to be N-hydroxy-FAF greater than N-hydroxy-AAF greater than N-hydroxy-PAF. A similar order of mutagenicity was demonstrated without an external metabolic activation system. These data demonstrate that the presence of two distinct enzymes in the rat mammary gland that activate arylhydroxamic acids.

2-Acetylaminofluorene↗
PubMed1982

Career goals and expectations of men and women pharmacy residents.

Personal and professional characteristics of men and women hospital pharmacy residents were studied to identify differences that could affect future hospital pharmacy practice. Residents in 111 ASHP-accredited pharmacy residency programs received a survey containing questions on demographic information, reasons for selecting a residency, areas of professional interest, postresidency career goals, responsibilities to home and family, and advantages and disadvantages associated with gender. Of 286 residents receiving questionnaires, 226 responded; the percentages of men and women responding corresponded to the ratio of men and women in hospital pharmacy residencies. While men and women expressed educational goals that were not significantly different, more men than women had earned or were in the process of earning advanced degrees. No significant differences were evident between men's and women's plans for marriage and children, but 73% of the women indicated that they would take time out from their practice to raise children, compared with only 9% of the men. The majority of residents did not think their gender affected them in their residency programs, but in professional interactions more men saw gender as an advantage and more women as a disadvantage. Significantly more than women aspired to be hospital pharmacy directors. The results suggest that men are obtaining advanced training closer to the time they graduate from pharmacy school and that in the future women competing for promotions may be older than men competing for comparable positions. Those planning pharmacy staffing should consider the needs of women, and men, who expect to take time out from their careers for family responsibilities and possibly seek part-time positions when they return to the work force.

Adult↗
PubMed1982

Association of arylhydroxamic acid N,O-acyltransferase and genetically polymorphic N-acetyltransferase in established inbred rabbit strains.

Partially purified liver preparations from 17 inbred and partially inbred rabbit strains were assayed for polymorphic N-acetyltransferase (NAT) and arylhydroxamic acid N,O-acyltransferase (AHAT) activities. The AC/J, AX/J, B/J, WH/J, X/J, Y-l/J, III/J, IIIC/J, III/DwJ, IIIEP/J and IIIVO/J inbred strains were identified as rapid acetylators and had high AHAT activity. The ACEP/J, AXBU/J, OS/J, III/cdJ, IIIVO/ahJ and IIIVO/vptJ strains were identified as slow acetylators and had low AHAT activity. These findings provide added evidence for the hypothesis that polymorphic NAT and AHAT activities are properties of the same enzyme. Additional studies in five of the rapid acetylator strains showed that they had significantly higher levels of liver NAT activity towards other arylamine acetylator predictor drugs and carcinogens than did obligate heterozygous (Rr) rapid acetylators from our rabbit colony. This indicates that the inbred animals are homozygous (RR) rapid acetylators and that there is a gene-dose response difference between the two rapid acetylator genotypes. Availability of established inbred and partially inbred strains shown to possess both acetylator phenotypes enhances the opportunity for using the rabbit as a genetic model for evaluating the role of the isoniazid acetylator polymorphism as a host factor in arylamine-related carcinogenesis.

Acetyltransferases↗
PubMed1981

New syntheses of N-(guanosin-8-yl)-4-aminobiphenyl and its 5'-monophosphate.

N-Acetoxy-4-trifluoroacetylaminobiphenyl (N-acetoxy-TFAABP) reacted readily with Guo and GMP at neutrality in a one-step fashion to yield N-(guanosin-8-yl)4-aminobiphenyl (Guo-ABP) (I) and N(guanosin-8-yl)-4-aminobiphenyl-5'-monophosphate (GMP-ABP) (II), respectively. GMP-ABP could also be formed in much lower yield from the reaction of N-acetoxy-4-formylaminobiphenyl (N-acetoxy-FABP) with GMP (pH 7.0) under more rigorous conditions. Enzymatic hydrolysis of GMP-ABP with alkaline phosphatase in Tris buffer (pH 8.0) at 37 degrees C yielded Guo-ABP. Guo-ABP showed a brilliant blue fluorescence on exposure to 366 nm UV light and its UV absorption spectrum was identical to that of Guo-ABP prepared by Kriek via a different route. Elemental analysis and nuclear magnetic resonance (NMR) data further confirmed the identity of this compound.

Aminobiphenyl Compounds↗
PubMed1981

Arylhydroxylamine-induced ribonucleic acid chain cleavage and chromatographic analysis of arylamine-ribonucleic acid adducts.

Reaction of N-hydroxy-2-aminofluorene (N-OH-AF) with rRNA at pH 5.0 decreased the molecular weight of the polynucleotide. Toluene-soluble aryl derivatives were released on hydrolysis of fluorenylamine- and biphenylamine-substituted RNA by treatment with venom phosphodiesterase and alkaline phosphatase. These data suggested that arylhydroxylamines, activated by incubation at pH 5.0 or by enzymatic O-acetylation, might react with the phosphate group of RNA to give unstable phosphate triesters. Spontaneous hydrolysis of these triesters would result in cleavage of the polynucleotide chain. Further enzymatic hydrolysis of the phosphate esters would yield nonpolar arylamine derivatives. Enzymatically degraded 4-aminobiphenyl(ABP)-RNA adducts were examined by high performance liquid chromatography (HPLC) for the presence of a putative phosphorylated adduct. Synthetic standards of the C-8-guanosine monophosphate-ABP adduct (ABP-GMP) and o-aminobiphenyl-O-phosphate were used as markers in the analysis of the digested RNA. A phosphate adduct of ABP was undetectable by these methods. The data also indicated that the ABP-GMP formed in the acyltransferase-mediated binding of N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) to RNA is readily degraded during the enzymatic digestion of the RNA adduct.

Amines↗
PubMed1981

Relationship of metabolic activation of N-hydroxy-N-acylarylamines to biological response in the liver and mammary gland of the female CD rat.

Intraperitoneal injection of the N-formyl, N-acetyl, or N-propionyl derivatives of N-hydroxy-4-aminobiphenyl, N-hydroxy-2-acetylaminofluorene, or N-(4-biphenyl)glycolamide disclosed that the ability of these compounds to induce mammary tumors in the female CD rat was greater if the compound was able to be metabolized to a reactive product by one of two soluble enzymes obtained from both the liver and mammary gland. A similar but weaker association between the formation of gamma-glutamyltranspeptidase-positive foci and cellular altered foci of the liver was also observed. The enzyme related to the tumorigenicity of these compounds was characterized by a highly specific capacity to form adducts from the acetyl and propionyl derivatives. The other enzyme exhibited greater activity with N-formyl substrates. The two enzyme activities were separable by ion-exchange chromatography on DEAE-cellulose and by gel filtration on Sephacryl. Liver microsomes also possessed the capacity to activate both the formyl and acetyl derivatives to reactive species; formyl substrates were 7 to 8 times more active than acetylated compounds. The microsomal activities and the formyl-preferring soluble enzyme were inhibited by diethyl-p-nitrophenylphosphate, a microsomal deacylase inhibitor. The cytosolic enzymes that are most active with the acetyl and propionyl substrates were little affected by this organophosphate compound. The microsomal activation was not due solely to deacylation of the hydroxamic acid, since formylated and acetylated substrates were hydrolyzed at approximately the same rates.

2-Acetylaminofluorene↗
PubMed1981

Activation of N-hydroxyphenacetin to mutagenic and nucleic acid-binding metabolites by acyltransfer, deacylation, and sulfate conjugation.

N-Hydroxyphenacetin was activated to a mutagen in the Salmonella-Ames test by rabbit liver acyltransferase, rat liver cytosol, and rat liver microsomes. N-[ring]3H]-Hydroxyphenacetin was bound to transfer RNA when activated by acyltransferase from rabbit or rat liver or rat liver microsomes. The acyltransferase-catalyzed binding was not inhibited by paraoxon, a deacetylase inhibitor. The use of N-hydroxyphenacetin radioactively labeled in the acetyl group, as well as the ring, indicated that deacetylation was involved in the microsome-catalyzed binding reaction. In addition, the microsome-catalyzed binding was inhibited 90% by paraoxon. p-Nitrosophenetole, a deacetylated derivative of N-hydroxyphenacetin, was synthesized and bound to transfer RNA without enzymatic activation. Activation of N-hydroxyphenacetin by sulfate conjugation was also found to lead to binding to transfer RNA. The data implicated acyl transfer, deacetylation, and sulfate conjugation as possible routes for the activation of N-hydroxyphenacetin.

Acyltransferases↗
PubMed1981

Effects of partial hepatectomy and dietary phenobarbital on liver and mammary tumorigenesis by two N-hydroxy-N-acylaminobiphenyls in female CD rats.

The objective of this study was to investigate the induction of liver tumors by arylhydroxamic acids. The potential involvement of sulfate conjugation was minimized by the administration of a N-hydroxy-4-acylaminobiphenyl to female CD rats. This experimental design provided for the exposure of a target organ that has only a low capacity for activation of hydroxamic acids by sulfate conjugation, with a carcinogen that does not induce tumors in liver that possess a high sulfotransferase activity. A single dose of the N-formyl or N-acetyl derivatives of N-hydroxy-4-aminobiphenyl was given i.p. at 0.4 mmol/kg body weight to 34-day-old animals. In attempts to amplify the hepatocarcinogenic potential of the compounds, partial hepatectomy 24 hr before the chemical injection and subsequent long-term treatment with phenobarbital in the diet were carried out. For comparative purposes, other animals were subjected to three additional partial hepatectomies subsequent to the carcinogen administration instead of the phenobarbital treatment. The experiments were terminated 64 weeks after injection. Both the N-formyl and N-acetyl derivatives of N-hydroxy-4-aminobiphenyl, in conjunction with partial hepatectomy and subsequent treatment of dietary phenobarbital, induced a high incidence of neoplastic nodules and gamma-glutamyltranspeptidase-positive foci in the liver. Only one hepatocellular carcinoma was observed in each treatment group. Repeated partial hepatectomies enhanced the yield of gamma-glutamyltranspeptidase-positive foci but were ineffective in producing neoplastic nodules. In addition to the liver lesions, mammary tumors were also induced. Importantly, an inhibitory effect of the subsequent administration of phenobarbital was observed on mammary tumor formation, possibly because of alterations in hormone metabolism resulting from the induction of microsomal enzymes by phenobarbital, which resulted in a decreased promoting effect. There was no difference in the tumorigenicity of the formyl and acetyl derivatives in these experiments.

Aminobiphenyl Compounds↗
PubMed1981

Formation, metabolic activation by N, O-acyltransfer, and hydrolysis of N-acyl-N-arylamine derivatives.

Amines and hydroxylamines can be produced from N-substituted aryl compounds by many organisms. Both functional groups can by N-acetylated enzymatically be preparations from the tissues of most mammalian species. The N-acylated products are subject to further metabolism including oxidation, hydrolysis, conjugation, or, with arylhydroxamic acids, N-O-acyltransfer. These reactions are of concern because they lead to changes in the levels of compounds that can alter tissue macromolecules. Select N-hydroxyarylamines and N-acyloxyarylamines can react with nucleic acid, and the hydroxylamines are mutagenic in bacterial systems. Thus the relative rates of these biochemical reactions within an organism may determine whether exposure to an arylamine will cause an adverse biologic effect. The ability of an arylamine to induce tumors reflects the composite effects of genetic determinants (i.e., species, strain, sex, and organ) as well as exposure to xenobiotic compounds because these factors modulate the metabolic pathways crucial to the carcinogenic process. The extreme genetic differences in the levels of the enzymes involved in the metabolism of N-acyl derivatives of arylamines in man and experimental animals offers an experimental approach that may aid in elucidating the mechanisms by which these compounds induce cancer.

Acetyltransferases↗
PubMed1980

Evidence that arylhydroxamic acid N,O-acyltransferase and the genetically polymorphic N-acetyltransferase are properties of the same enzyme in rabbit liver.

Arylhydroxamic acid N,O-acyltransferase and Co-ASAc-dependent N-acetyltransferase activities were measured simultaneously in liver cytosols from rabbits of known acetylator phenotype. Both activities were high in rapid acetylator rabbits and low in slow acetylator rabbits indicating that these two acetyl transfer steps in the metabolic activation of certain arylamines are under common genetic control in this species. The two enzyme activities could not be resolved by sequential centrifugation, fractional precipitation with ammonium sulfate, ion exchange chromatograhy on DEAE-cellulose, gel filtration on Sephacryl, and electrophoresis on polyacrylamide gels. Sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis of extracts of disc gel electrophoretic slices showed that a single symmetrical protein band with a molecular weight of 33,000 was associated with both activities. The results obtained strongly suggest that the CoASAc-dependent N-acetyltransferase reaction and the intramolecular N,O-acetyl transfer by arylhydroxamic acid N,O-acyltransferase are properties of the same enzyme.

Acetyltransferases↗
PubMed1979

Phenacetin studies.

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Acute Kidney Injury↗
PubMed1979

Metabolic activation of arylhydroxamic acids by N-O-acyltransferase of rat mammary gland.

The lactating mammary glands of rats contain an arylhydroxamic acid N,O-acyltransferase that catalyzes the formation of arylamine-substituted nucleic acid on incubation with N-hydroxy-N-2-acetylaminofluorene or N-hydroxy-N-4-acetylaminobiphenyl and transfer RNA. The acyltransferase activity migrates as a single component with a molecular weight of 28,000 on gel filtration on Sephadex G-100. Acyltransferase activities of the lactating mammary glands of Sprague-Dawley animals are approximately twice those of the less susceptible Fischer strain as determined by assay with either hydroxamic acid. The fluorene substrate was 15 times as efficient as the biphenyl compound in promoting adduct formation. Ribosomal RNA adducts formed in vivo after administration of N-hydroxy-N-2-acetylaminofluorene were consistent with an acyltransferase mechanism of activation in that the adducts did not retain the acetyl group.

Acyltransferases↗