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Y Yamazoe

Publications and source records attributed to Y Yamazoe.

At least 163 records · Page 9Linked to original sources
PubMed1986

Inhibition of acetyl-coenzyme A dependent activation of N-hydroxyarylamines by phenolic compounds, pentachlorophenol and 1-nitro-2-naphthol.

Pentachlorophenol (PCP) and 1-nitro-2-naphthol were found to be potent inhibitors of enzymatic acetyl-CoA dependent activation, which is suggested as proceeding through direct O-acetylation, of N-hydroxyarylamines to tRNA binding by liver cytosolic enzymes from hamsters and rats. IC50 values of PCP for the activation of 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-OH-Glu-P-1), 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) and N-hydroxy-2-aminofluorene (N-OH-AF) were 20, 25 and 17 microM, respectively, in hamster cytosol system. Similar inhibition was observed with rat liver cytosol (IC50 values of PCP and 1-nitro-2-naphthol were 13 and 12 microM, respectively, for the binding of N-OH-Glu-P-1). PCP is known as an inhibitor of sulfotransferase; however, another potent inhibitor of sulfotransferase, 2,6-dichloro-4-nitrophenol, did not inhibit the acetyl-CoA dependent binding. Antibiotic thiolactomycin, which inhibits bacterial O-acetyltransferase, did not affect the activation by hamster and rat cytosol, indicating the difference in property between bacterial and mammalian enzymes. The kinetic data obtained with hamster cytosol suggested the competitive inhibition of PCP with substrate, N-OH-Glu-P-1, and non-competitive inhibition with acetyl-CoA. In addition to the O-acetylation, PCP and 1-nitro-2-naphthol also inhibited N-acetylation of arylamines and N,O-acetyltransfer reaction of N-hydroxy-2-acetylaminofluorene (N-OH-AAF) by hamster cytosol. IC50 values for these two types of acetyltransfer reactions, however, were slightly higher than those observed for acetyl-CoA dependent activations of N-hydroxyarylamines.

Acetyl Coenzyme A↗
PubMed1986

Reactivity of benzidine diimine with DNA to form N-(deoxyguanosin-8-yl)-benzidine.

Benzidine diimine (BZDI), a reactive intermediate in the metabolic peroxidation of the carcinogen benzidine, has been reported to bind covalently to cellular proteins and nucleic acids. We have examined the nature of this interaction with DNA and have identified a major carcinogen-nucleoside adduct. BZDI (20-50 microM) reacted rapidly with DNA in vitro to give relatively high levels of covalently bound products (1-2 adducts/10(3) nucleotides; 30-45% yield). The binding was completely inhibited by addition of glutathione but was unaffected by acidic pH, air, free radical traps, or strong nucleophiles. Upon enzymatic hydrolysis of the BZDI-modified DNA and subsequent h.p.l.c., a major adduct was isolated and characterized by u.v., mass and proton magnetic resonance spectroscopy as N-(deoxyguanosin-8-yl)-benzidine. The identity of this adduct and its formation under various incubation conditions suggest a reaction mechanism that involves a simple deprotonation of the cationic diimine, formation of an electrophilic arylnitrenium ion, and covalent binding to guanine in the DNA.

Animals↗
PubMed1986

The regulation by growth hormone of microsomal testosterone 6 beta-hydroxylase in male rat livers.

The relationship between growth hormone and testosterone (T) 6 beta-hydroxylase was investigated in normal and hypophysectomized (hypox) male rats. The administration of human growth hormone (hGH) by either intermittent injections or continuous infusion to normal and hypox rats decreased the activity of T 6 beta-hydroxylase in hepatic microsomes. Hypophysectomy did not reduce, but rather increased the 6 beta-hydroxylase activity, while the 16 alpha-hydroxylase activity decreased. These results, together with the data from a Western blot, indicate that growth hormone acts as a repressive factor for the expression of T 6 beta-hydroxylase in a manner different from the regulation of T 16 alpha-hydroxylase.

Animals↗
PubMed1986

Effect of growth hormone and ectopic transplantation of pituitary gland on sex-specific forms of cytochrome P-450 and testosterone and drug oxidations in rat liver.

The effects of growth hormone and ectopic transplantation of pituitary gland on the amounts of sex-specific cytochrome P-450, P-450-male and P-450-female, and the activities of testosterone and drug hydroxylases in male rat liver microsomes were studied. Hypophysectomy decreased the content of P-450-male, without changing the total cytochrome P-450 level. The continuous infusion of growth hormone into hypophysectomized rats and the transplantation of pituitary gland under the renal capsule caused a further decrease in P-450-male content and an expression of P-450-female. In contrast, the intermittent injection of growth hormone into hypophysectomized rats increased P-450-male content to the level seen in intact male rats. The activities of testosterone 2 alpha- and 16 alpha-, but not 6 beta-, 7 alpha-, or 15 alpha-hydroxylase, were changed in association with the level of P-450-male by these treatments. Anti-P-450-male immunoglobulin G inhibited testosterone 2 alpha- and 16 alpha-hydroxylations, but not 6 beta-, 7 alpha- or 15 alpha-hydroxylation. These results indicate that growth hormone regulates the expression of P-450-male responsible for testosterone 2 alpha- and 16 alpha-hydroxylations. The metabolism of 7-propoxycoumarin, benzo(a)pyrene and aminopyrine also changed with the content of P-450-male, although the correlation was less than that observed with testosterone 2 alpha- and 16 alpha-hydroxylation.

Animals↗
PubMed1986

Effects of hypophysectomy and growth hormone treatment on sex-specific forms of cytochrome P-450 in relation to drug and steroid metabolisms in rat liver microsomes.

Hypophysectomy decreased the content of a male specific cytochrome P-450, P-450-male, in male rats, while it expressed P-450-male and completely depressed a female specific cytochrome P-450, P-450-female, in female rats. Intermittent injections of human growth hormone (GH), which mimic the secretion in males, restored P-450-male in hypophysectomized (Hypox) male rats and partially restored P-450-female in Hypox female rats. Continuous infusion of GH, which mimics the female secretion pattern, into Hypox male rats caused a further decrease in P-450-male content, and it caused the expression of P-450-female. In Hypox female rats, the same treatment depressed P-450-male and expressed P-450-female to the level of an intact female. These results indicate that the diurnal changes in the pattern of serum growth hormone level regulate the expression of P-450-male and P-450-female. The activities of testosterone 2 alpha- and 16 alpha-hydroxylases were closely correlated to P-450-male content with the correlation coefficients (r) of 0.955 and 0.929, respectively. Benzo(a)pyrene hydroxylation was also correlated to P-450-male content (r = 0.850). Aminopyrine N-demethylation and propoxycoumarin O-depropylation were correlated to less extents (r = 0.692 and r = 0.720), while aniline hydroxylation and O-ethylresorufin O-deethylation were not correlated to P-450-male content. These results indicate that testosterone 2 alpha- and 16 alpha-hydroxylations are closely dependent, but the metabolism of a variety of drugs are dependent to different extents on P-450-male in rat liver microsomes.

Animals↗
PubMed1986

Acetyl coenzyme A dependent activation of N-hydroxy derivatives of carcinogenic arylamines: mechanism of activation, species difference, tissue distribution, and acetyl donor specificity.

Acetyl coenzyme A dependent activation of 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-OH-Glu-P-1) and 3-hydroxyamino-1-methyl-5H-pyrido [4,3-b]indole (N-OH-Trp-P-2) was investigated using cytosols from hepatic and extrahepatic tissues of various animal species in comparison with that of N-hydroxy-2-aminofluorene. N-OH-Glu-P-1 and N-OH-Trp-P-2 were metabolized to the reactive species capable of binding to transfer RNA through a putative O-acetylation process by liver cytosols. Kidney, small intestinal mucosa, lung, and bladder from hamsters and rats also mediated the reaction, although their activities were lower than that in the liver. Marked species differences in the enzymatic activities of livers were observed. Hamsters showed the highest ability in the activation for N-OH-Glu-P-1 and N-OH-Trp-P-2, followed by rats. Rabbits with a rapid acetylator phenotype, which showed a high activity in the N-acetylation of arylamines, activated N-OH-Glu-P-1 but scarcely N-OH-Trp-P-2. A rabbit with a slow acetylator phenotype, mice, guinea pigs, and a dog showed marginal or nondetectable activities with N-OH-Glu-P-1 and N-OH-Trp-P-2. A typical nonheterocyclic N-hydroxyarylamine, N-hydroxy-2-aminofluorene was also activated by the acetyl coenzyme A dependent system to an intermediate which bound to transfer RNA. However, the acetyl-CoA dependent binding of N-hydroxy-2-aminofluorene was markedly different from those observed with N-OH-Glu-P-1 and N-OH-Trp-P-2 concerning the order of activities among animal species used. In addition to short chain acyl coenzyme As, N-hydroxy-2-acetylaminofluorene also served as an acetyl donor for the activation of N-OH-Glu-P-1 and N-OH-Trp-P-2 in liver cytosol systems. The formation of N-acetyl-N-OH-Glu-P-1, however, was not detected in the cytosolic system of N-OH-Glu-P-1 with acetyl-CoA, suggesting the direct O-acetylation at the N-hydroxy group as a major pathway for the activation of N-hydroxyarylamines.

Acetyl Coenzyme A↗
PubMed1985

DNA binding of N-hydroxy-Trp-P-2 and N-hydroxy-Glu-P-1 by acetyl-CoA dependent enzyme in mammalian liver cytosol.

3-Hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole and 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, active metabolites of protein pyrolysate carcinogens, were further activated to DNA-binding species by an acetyl-CoA dependent enzyme in hepatic cytosol. This activity was supported also by N-hydroxy-2-acetylaminofluorene instead of acetyl-CoA, and it was inhibited by iodoacetamide and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) but not by diethyl-p-nitrophenylphosphate. The activity was observed in the cytosols of rats, mice and rapid acetylator rabbits, which possessed N-acetylation activity of 2-aminofluorene and Trp-P-2. On the other hand, the activity could not be detected in the cytosols of a dog and a slow acetylator rabbit.

Acetyl Coenzyme A↗
PubMed1985

DNA adducts formed by ring-oxidation of the carcinogen 2-naphthylamine with prostaglandin H synthase in vitro and in the dog urothelium in vivo.

The presence of relatively high levels of prostaglandin H synthase (PHS) in the dog urinary bladder and its ability to mediate the activation of carcinogenic arylamines to DNA-bound products in vitro suggests the involvement of this enzyme in arylamine-induced bladder carcinogenesis. Since the PHS-dependent metabolism of 2-naphthylamine (2-NA) had been shown to yield both ring- and N-oxidation products in vitro, we compared the reactivity of 3H-labeled N-hydroxy-2-naphthylamine (N-OH-2-NA), 2-nitrosonaphthalene, and 2-amino-1-naphthol (2-AN) toward DNA and protein. In the PHS-incubation system, all three derivatives bound at high levels to protein, but only N-OH-2-NA and 2-AN bound appreciably to DNA. Though ring-oxidation has usually been considered a detoxification pathway, the covalent binding of [3H]2-AN to DNA was found to occur readily under aerobic conditions and was enhanced at acidic pH. At pH 5 in air, the reactivity of [3H]2-AN with nucleic acids and protein was in the order: serum albumin greater than tRNA greater than poly G greater than poly C greater than DNA greater than poly A greater than rRNA greater than poly U. Enzymatic hydrolysis of DNA reacted with [3H]2-AN and subsequent analysis by h.p.l.c. indicated the presence of several carcinogen-nucleoside adducts. The major product was characterized as N4-(deoxyguanosin-N2-yl)-2-amino-1,4-naphthoquinoneimine; and two minor products were tentatively identified as N4-(deoxyadenosin-N6-yl)-2-amino-1,4-naphthoquinoneimine and a deoxyguanosin-N2-yl adduct of a naphthoquinoneimine dimer. These adducts accounted for approximately 60% of the total DNA binding obtained by incubation of [3H]2-NA with PHS in vitro and for approximately 20% of the [3H]2-NA bound to dog urothelial DNA in vivo. The remaining adducts were identical to those previously reported as products of the reaction of N-OH-2-NA with DNA. These results suggest that a minor proportion of the DNA adducts found in vivo may be formed by PHS-activation of 2-NA in the target tissue. Furthermore, the reactivity of 2-AN with cellular nucleophiles, presumably through formation of 2-imino-1-naphthoquinone or a protonated 4-naphthocarbenium ion, indicates that ring-oxidation products of arylamines and of other carcinogenic aryl compounds should be evaluated as proximate carcinogenic metabolites.

2-Naphthylamine↗
PubMed1985

Fast-atom bombardment and electron-impact mass spectrometry of N-hydroxyarylamines, active intermediates of mutagenic aromatic amines.

Thermally labile N-hydroxyarylamines, which are the active metabolites of carcinogenic/mutagenic aromatic amines and show potent direct mutagenicity, were studied by fast-atom bombardment (F.A.B.) mass spectrometry and electron-impact (E.I.) mass spectrometry. The protonated molecular ion [M + H]+ and the molecular ion [M]+ were observed at high intensity in the F.A.B. mode. The fragment ions corresponding to [M + H-16]+, [M + H-17]+ and [M-16]+, [M-17]+, [M + H-32]+ and [M-32]+ were also observed characteristically. The quasimolecular ion peaks were shifted up by the numbers of active hydrogens in molecules after the hydrogen-deuterium exchange with [hydroxy--2H3]glycerol and 2H2O. The formation of the ions continued stably throughout the period of measurement, and the decomposition of the samples did not occur in the F.A.B. ion source, compared with the E.I. mode. Hence, it is suggested that the F.A.B. technique is useful for the analysis of the heat-labile toxicologically important N-hydroxyarylamines.

Amines↗
PubMed1985

Catalysis of the covalent binding of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole to DNA by a L-proline- and adenosine triphosphate-dependent enzyme in rat hepatic cytosol.

An enzymatic mechanism involved in the activation of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-hydroxy-Trp-P-2), a mutagenic intermediate of a tryptophan pyrolysate, was studied in vitro. In hepatic cytosol supplemented with adenosine triphosphate and L-proline, N-hydroxy-Trp-P-2 was converted to a form which reacts readily with DNA. The enzyme responsible for the activation was partially purified and identified as prolyl transfer RNA synthetase as judged by their cofactor requirements, inhibition by pyrophosphate or adenosine monophosphate, and copurification of their activities. The prolyl transfer RNA-dependent covalent binding of N-hydroxy-Trp-P-2 to DNA of hepatic cytosol was highest in rats, followed by mice, hamsters, rabbits, and guinea pigs in that order. The capacity for the binding of N-hydroxy-Trp-P-2 was largely consistent with their prolyl transfer RNA synthetase activity. With regard to the ultimate form of N-hydroxy-Trp-P-2 for the covalent binding, a possible formation of N,O-prolyl-3-amino-1-methyl-5H-pyrido[4,3-b]indole was proposed.

Adenosine Triphosphate↗
PubMed1984

Inhibition of benzodiazepine and GABA receptor binding by amino-gamma-carbolines and other amino acid pyrolysate mutagens.

The effect of several pyrolysate mutagens on the benzodiazepine and GABA receptors was investigated. Of amino-gamma-carbolines, Trp-P-1 antagonized the suppressive effect of diazepam on the pentylenetetrazol-induced convulsions and death, whereas Trp-P-2 by itself precipitated seizures and death in male mice. Both Trp-P-1 and Trp-P-2 inhibited the specific binding of [3H]diazepam and [3H]muscimol in rat brain membranes mainly by increasing Kd, indicating that these gamma-carbolines bind on benzodiazepine and GABA receptors. IC50S of Trp-P-1 and Trp-P-2 on specific [3H]flunitrazepam binding were not changed by addition of GABA. The Hill coefficient of Trp-P-1 for displacing [3H]diazepam binding was about unity whereas that of Trp-P-2 was less than unity. These results suggest that Trp-P-1 and Trp-P-2 act as active antagonists or inverse agonists at benzodiazepine receptors. The convulsant effect of the gamma-carbolines may be mediated by an action on the central benzodiazepine receptors; however, the role of the effect on GABA receptors is not clear.

Animals↗
PubMed1984

Species differences in the N-acetylation by liver cytosol of mutagenic heterocyclic aromatic amines in protein pyrolysates.

The N-acetylation of 3-amino-1-methyl-5H-pyrido[4,3-b]-indole (Trp-P-2) and other heterocyclic aromatic amine promutagens isolated originally from protein pyrolysates was investigated using liver cytosols from various animal species and acetyl-CoA as an acetyl donor. Marked species differences in the enzymatic N-acetylation activity of these heterocyclic amines were observed. The N-acetylation activity also varied among the substrates used. The N-acetylation of these heterocyclic amines by hepatic cytosols from all animal species used was much less than that of the non-heterocyclic aromatic amine carcinogen, 2-aminofluorene (2-AF): the N-acetylation of Trp-P-2 was more than one hundred times less than that of 2-AF. These results suggested that the metabolic activation pathway of these mutagenic heterocyclic amines is different from that of 2-AF. The hamster but not rat cytosol showed the ability to utilize N-hydroxy-2-acetylaminofluorene and 2-acetylaminofluorene as acetyl donor in the N-acetylation of Trp-P-2.

Acetylation↗
PubMed1984

Glutathione transferase-mediated and non-enzymatic activation and detoxication of the N-hydroxy derivative of Trp-P-2, a potent pyrolysate promutagen.

Glutathione (GSH) transferase-mediated and non-enzymatic activation and detoxication of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) were studied in vitro. N-OH-Trp-P-2 is an active metabolite of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), a mutagenic and carcinogenic heterocyclic amine. The enzymatic GSH conjugation with N-OH-Trp-P-2 was catalysed by rat-liver GSH transferase and a rat-liver cytosol fraction to form three conjugates (CH-1, CH-2 and CH-3). The mutagenicities of the GSH conjugates were studied by using Salmonella typhimurium TA98 as the tester strain. The GSH conjugates except for CH-3 were completely detoxicated products, but CH-3 was found to be a more potent mutagen than N-OH-Trp-P-2. The mutagenicity of CH-3 seemed to be due to the direct action of the conjugate, but not to N-OH-Trp-P-2 formed from it.

Animals↗
PubMed1984

Specificity of four forms of cytochrome P-450 in the metabolic activation of several aromatic amines and benzo[a]pyrene.

The involvement of four forms of cytochrome P-450 in the activation of the promutagens, 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminofluorene and 4-aminobiphenyl has been investigated using a Salmonella test system. A high-spin form, P-448 II-a, catalysed the activation of IQ and Glu-P-1 28 and 12 times faster, respectively, than a low-spin form, P-448 II-d, whereas benzo[a]pyrene was metabolized to the phenols 60 times faster by P-448 II-d than P-448 II-a. Both P-448 II-a and P-448 II-d were highly active in the activation of Trp-P-2 and 2-aminofluorene. Treatment of CDF1 mice with polychlorinated biphenyls (PCB) increased the microsomal-activating ability for the promutagens in various degrees. More than a ten-fold increase was observed with Trp-P-2, while the increase was only two-fold with IQ. No sex-related difference was observed for the hepatic microsomal activating ability of male and female CDF1 mice for Trp-P-2, Glu-P-1 or IQ. These results indicate that more than two forms of cytochrome P-450, which are inducible by treatment with PCB or 3-methylcholanthrene, mediate the metabolic activation of heteroaromatic amines in rats and mice.

Amines↗
PubMed1983

Mechanism of activation of proximate mutagens in Ames' tester strains: the acetyl-CoA dependent enzyme in Salmonella typhimurium TA98 deficient in TA98/1,8-DNP6 catalyzes DNA-binding as the cause of mutagenicity.

The mechanism of activation of proximate mutagens in Ames' tester strains was described. 2-Hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-OH-Glu-P-1) and 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) were activated to DNA-binding species in the presence of acetyl-CoA by the enzyme(s) in Salmonella typhimurium TA98, and this enzyme was deficient in TA98/1,8-DNP6. Mutagenicity of N-OH-Glu-P-1 to TA98/1,8-DNP6 was much lower than that to TA98. Therefore, it was demonstrated that the acetyl-CoA dependent enzyme(s) activated N-OH-Glu-P-1 to the active form which could covalently bind to DNA and subsequently caused mutagenicity.

Acetyl Coenzyme A↗
PubMed1983

A high spin form of cytochrome P-448 highly purified from PCB-treated rats--II. Characteristic requirement of cytochrome b5 for maximum activity.

A high spin form of cytochrome P-448 (PCB P-448-H), highly purified from microsomes of PCB-treated rats, catalyzed oxidations of several compounds and required cytochrome b5 for its full activities in all oxidations examined. PCB P-448-H catalyzed the hydroxylation of aniline and O-dealkylations of p-alkoxy derivatives of aniline and nitrobenzene and 7-alkoxy derivatives of coumarin. Among the activities measured, hydroxylation of aniline and O-dealkylation of p-alkoxy derivatives of aniline were catalyzed by PCB P-448-H more efficiently than by PCB P-448-L, which was a low spin form of cytochrome P-448 purified from liver microsomes of PCB-treated rats. In all reactions, PCB P-448-H required cytochrome b5 for maximum activity. Slight requirements were also seen with PCB P-448-L but varied equivocally depending on the substrates. Cytochrome b5 showed its maximum effects on p-propoxyaniline O-depropylation activity at a molar ratio of cytochrome b5 to PCB P-448-H of 1:2. The enhancement by cytochrome b5 was more pronounced when lower concentrations of either the substrate or NADPH-cytochrome P-450 reductase were added to the reconstituted system. Based on these results, we confirm that PCB P-448-H is a unique form of cytochrome P-448 with respect to the requirements for cytochrome b5 and is a good probe to study the mechanisms involved in the enhancement of drug oxidations by cytochrome b5.

Animals↗
PubMed1983

Interactions between the active metabolite of tryptophan pyrolysate mutagen, N-hydroxy-Trp-P-2, and lipids: the role of lipid peroxides in the conversion of N-hydroxy-Trp-P-2 to non-reactive forms.

The interactions between lipids and the mutagenic active metabolite of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-hydroxy-Trp-P-2), were studied. Oleic acid showed an inhibitory effect on the formation of this active metabolite mainly by inhibition of hepatic microsomal oxidation systems. On the other hand, microsomal lipids from rat liver and commercial pig liver lecithin diminished the amount of N-hydroxy-Trp-P-2 without inhibiting the metabolism of Trp-P-2. The direct reaction of these lipids with N-hydroxy-Trp-P-2 was disclosed by experiments using N-hydroxy-Trp-P-2 and lipids without microsomes. Furthermore, the participation of lipid peroxides in this reaction was suggested by a linear relationship between the concentrations of the conjugated diene of lipids and the disappearance of N-hydroxy-Trp-P-2. When [3H]N-hydroxy-Trp-P-2 was incubated in the presence of pig liver lecithin, the polar products which were not formed in the incubation without lipids were newly detected by thin-layer chromatography (TLC) analysis.

Animals↗