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Biomedical subjects

H Yagi

Publications and source records attributed to H Yagi.

At least 397 records · Page 22Linked to original sources
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

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

Binding of K- and non-K-region arene oxides and phenols of polycyclic hydrocarbons to polyguanylic acid.

Arene oxide derivatives of carcinogenic polycyclic hydrocarbons have been postulated as the reactive intermediates responsible for the in vivo binding of the parent hydrocarbon to cellular nucleic acids. In this study the reaction of 12 different K- and non-K-region arene oxides and 7 benzo(a)pyrene phenols with polyguanylic acid in aqueous acetone solutions has been investigated. The extent of binding of the polycyclic hydrocarbon was monitored by changes in the ultraviolet absorption and fluorescence spectra of the reisolated polyguanylic acid. The most reactive compound was the K-region arene oxide of 7,12-dimethylbenz(a)anthracene. A lower but significant level of binding was detected with the K-region arene oxides of benz(a)anthracene, benzo(a)pyrene, and 3-methylcholanthrene. Very low or negligible binding was detected with the K-region arene oxides of pyrene and phenanthrene; the non-K-region arene oxides of benzo(a)pyrene, phenanthrene, and naphthalene; and all of the benzo(a)pyrene phenols. Significant differences in the fluorescence spectra of polyguanylic acid modified with three different benzo(a)-pyrene arene oxides were observed.

9,10-Dimethyl-1,2-benzanthracene↗
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

Mutagenic and cytotoxic activity of benzol[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols.

The benzo[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols (4-, 5-, 7-, 8-, 9-, and 10-hydroxybenzo[a]pyrene) have been tested for mutagenic and cytotoxic activity in bacteria and in a mammalian cell culture system. Benzo[a]pyrene 4,5-oxide (K-region) was highly mutagenic in two histidine-dependent strains (TA1537 and TA1538) of Salmonella typhimurium which detect frameshift mutagens. In contrast, benzo[a]pyrene 7,8- and 9,10-oxides were less than 1% as mutagenic as the 4,5-oxide. Benzo[a]pyrene 7,8- and 9,10-oxides were unstable in aqueous media, whereas the 4,5-oxide was stable for several hours. This difference in stability could not account for the different mutagenic activities of the three arene oxides. The benzo[a]pyrene oxides were inactive in a strain (TA1535) that is reverted by base pair mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine or in a strain (TA1536) that detects framshift mutagens similar to the acridine half-mustard ICR-191. Benzo-[a]-pyrene and the six phenols were all stable in aqueous media, but they had little or no mutagenic activity in any of the four Salmonella strains. Conversion of 8-azaguanine-sensitive Chinese hamster V79 cells to 8-azaguanine-resistant variants was increased by benzo[a]pyrene 4,5-oxide, whereas the 9,10-oxide was considerably less active. Benzo[a]pyrene and the other derivatives had little or no effect. Benzo[a]yrene 4,5-oxide was more cytotoxic to the Chinese hamster V79 cells than the 7,8- and 9,10-oxides, while 8-hydroxybenzo[a]pyrene was the most cytotoxic of the six phenols.

Benzopyrenes↗
PubMed1974

Effects of inducers and epoxide hydrase on the metabolism of benzo(a)pyrene by liver microsomes and a reconstituted system: analysis by high pressure liquid chromatography.

The mobilities of 24 potential metabolites of benzo[a]pyrene were examined with high pressure liquid chromatography. Twelve phenols, five quinones, four dihydrodiols, and three oxides were studied. The chromatographic procedure employed allowed the separation and quantitation of benzopyrene metabolites into three major groups consisting of phenols, quinones, and dihydrodiols. Two of the benzopyrene oxides were unstable during chromatography, whereas the third oxide was more stable and chromatographed in the quinone fraction. Treatment of rats with phenobarbital or 3-methylcholanthrene enhanced the metabolism of benzopyrene by liver microsomes and altered the relative amounts of the various metabolites formed. In the absence of epoxide hydrase (EC 4.2.1.63), benzopyrene was metabolized primarily to phenols and quinones but was not appreciably metabolized to dihydrodiols by a solubilized, reconstituted cytochrome P-448 monooxygenase system. Addition of partially purified epoxide hydrase resulted in the formation of benzopyrene dihydrodiols with a concomitant decrease in the formation of phenolic metabolites, indicating that benzopyrene undergoes metabolism via arene oxides that are precursors for dihydrodiols and phenols.

Animals↗
PubMed1972

A novel mechanism for the NIH-shift.

Kinetics of aromatization of 1,4-dimethylbenzene oxide (I) to 2,5-dimethylphenol (II) and 2,4-dimethylphenol (III), the latter arising by an NIH-Shift of a methyl group, as measured in the pH range 1-12, follow the equation -d[I]/dt = [I][k(0) + (k[unk] + k[unk])aH], where k(0) = 4.8 x 10(-3) sec(-1), k[unk] = 7.3 x 10(2) M(-1) sec(-1), and k[unk] = 5.3 x 10(2) M(-1) sec(-1). The ratio of products II to III at pH >/= 6 in the spontaneous rearrangement (k(0)) is 13 to 87, and changes to 54 to 46 in the acid-catalyzed rearrangement (k[unk] and k[unk]). While no intermediate is detectable in the acid-catalyzed rearrangement of the arene oxide by pathway k[unk], simultaneous addition of water (and other nucleophiles) by pathway k[unk] leads, via the intermediate 1,4-dimethyl-2,5-cyclohexadiene-1,4-diol (IV), to the phenols II and III. This new mechanism for the NIH-Shift serves as a model for the ease of nucleophilic addition to other arene oxides, such as those of the polycyclic aromatic hydrocarbons recently implicated in mechanisms of carcinogenesis.

Alcohols↗