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Biomedical subjects

H Yagi

Publications and source records attributed to H Yagi.

At least 325 records · Page 18Linked to original sources
PubMed1981

Highly tumorigenic bay-region diol epoxides from the weak carcinogen benzo[c]phenanthrene.

In the four years since its inception, the bay-region theory has proved highly successful in predicting which diol epoxide of a polycyclic aromatic hydrocarbon would have the highest tumorigenic activity. The present studies on benzo[c]phenanthrene have shown this hydrocarbon to be unique. It is the first hydrocarbon for which the bay-region diol epoxide that has its benzylic hydroxyl group and epoxide oxygen cis (isomer-1 series) has significant tumorigenic activity. Additionally, its bay-region diol epoxides are the most tumorigenic diol epoxides yet tested on mouse skin despite their expected and observed very low chemical reactivity. Perhaps some unique feature of the shape of benzo[c]phenanthrene can account for the remarkable biological activity of its bay-region diol epoxides. The high degree of crowding in the bay-region of benzo[c]phenanthrene may be such a contributing factor. It is know, for example, that methyl-substitution in the bay-region but not on the critical benzo-ring enhances the tumorigenic activity of 7,12-dimethylbenzo[a]anthracene relative to 7-methylbenzo[a]anthracene (Newman, 1976), of 5-methylchrysene relative to chrysene (Hecht et al., 1974), and of 11-methylbenzo[a]pyrene relative to benzo[a]pyrene (Iyer et al., 1980). Steric crowding in the bay-region of benzo[c]phenanthrene (Hirshfeld, 1963) and 7,12-dimethylbenzo[a]anthracene has been shown by x-ray crystallography to cause out-of-plane deformation of their aromatic ring systems.

Animals↗
PubMed1981

Regio- and stereoselectivity of hepatic cytochrome P-450 toward polycyclic aromatic hydrocarbon substrates.

Although the cytochrome P-450 system shows broad substrate specificity toward the PAH, it also has regio- and stereoselectivity. Of the PAH substrates yet studied, phenanthrene is metabolized most efficiently, whereas chrysene and DBA are much more slowly turned over. Interestingly, the cytochrome P-450 system and epoxide hydrolase favor the formation of dihydrodiols with R,R configuration. The predominant enantiomers of the dihydrodiols with the bay-region double bond, as well as bay-region diol epoxides derived from phenanthrene, chrysene, BA and B[a]P, are superimposable when their bay-regions are aligned (Fig. 3). These metabolically favored isomers of the dihydrodiols and bay-region diol epoxides are also the more carcinogenic isomers when derived from carcinogenic polycyclic hydrocarbons.

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PubMed1981

Experimental study on the inhibition of kinin release in endotoxin shock by glutathione, proteinase inhibitors, hydrocortisone and hyperbaric oxygen.

Glutathione, proteinase inhibitors, steroids and hyperbaric oxygen are significantly effective to improve the survival of rats and to inhibit the liberation of plasma kinin in endotoxin shock. The combination of those anti-shock agents resulted in a decrease of kinin release in endotoxin shock in contrast with the treatment with each agent alone.

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PubMed1981

Mutagenicity of the bay-region diol-epoxides and other benzo-ring derivatives of dibenzo(a,h)pyrene and dibenzo(a,i)pyrene.

The mutagenic activities of dibenzo(a,h)(pyrene, dibenzo(a,i)pyrene, and a total of 11 of their benzo-ring derivatives were evaluated in bacterial and mammalian cells in the absence or presence of a mammalian metabolic activation system. trans-1,2-Dihydroxy-1,2-dihydrodibenzo(a,h)pyrene and trans-3,4-dihydroxy-3,4-dihydrodibenzo(a,i)pyrene, the expected dihydrodiol precursors of bay-region diol-epoxides, were metabolized to products which were more mutagenic to strains TA98 and TA100 of Salmonella typhimurium than were the metabolic products formed from their respective parent hydrocarbons. For each dihydrodiol, replacement of the benzo-ring double bond adjacent to the diol moiety with a single bond resulted in tetrahydrodiol derivatives which could not be metabolically activated, suggesting that one or both diastereomeric bay-region diol-epoxides were the bioactivated metabolites. The authentic bay-region diol-epoxide diastereomers of dibenzo(a,h)pyrene and dibenzo(a,i)pyrene in which the benzylic hydroxyl group and the epoxide oxygen are trans (diol-epoxide 2 series) were highly mutagenic in strains TA98 and TA100 of S. typhimurium and in cultured Chinese hamster V79 cells. Neither diol-epoxide was significantly, if at all, metabolized by epoxide hydrolase. The bay-region diol-epoxide of dibenzo(a,i)pyrene was from 1.5 to 5 times more active as a mutagen than the diol-epoxide of dibenzo(a,h)pyrene, and in strain TA98 of S. typhimurium as well as Chinese hamster V79 cells, it had activity comparable to that of the highly carcinogenic bay-region diol-epoxide of benzo(a)pyrene.

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PubMed1981

Species-specific enhancement by 7,8-benzoflavone of hepatic microsomal metabolism of benzo[e]pyrene 9,10-dihydrodiol to bay-region diol epoxides.

Metabolism of benzo[e]pyrene 9,10-dihydrodiol to the bay-region 9,10-diol-11,12-epoxides by hepatic microsomes from human, rat, mouse, guinea pig, hamster, and rabbit has been examined in the presence and absence of 7,8-benzoflavone. In the absence of 7,8-benzoflavone, the formation of bay-region diol epoxides from benzo[e]pyrene 9,10-dihydrodiol was low in all species except the hamster. With hamster liver microsomes, greater than 60% of total metabolites formed were bay-region diol epoxides, whereas human and mouse liver formed less than 5% of total metabolites as bay-region diol epoxides. Addition of 7,8-benzoflavone to the microsomal incubations stimulated the formation of diol epoxides, but this stimulation was species dependent. The most dramatic stimulation was observed with human and rabbit liver microsomes. In a parallel study, metabolic activation of benzo[e]pyrene 9,10-dihydrodiol to mutagens toward Salmonella typhimurium strain TA 100 by hepatic microsomes from the above species was examined in the presence and absence of 7,8-benzoflavone. In the absence of 7,8-benzoflavone, hepatic microsomes from all the species only weakly activated benzo[e]pyrene 9,10-dihydrodiol to mutagens. 7,8-Benzoflavone enhanced the metabolic activation catalyzed by microsomes from all species except rats and hamsters. Particularly high stimulation was observed with human and rabbit liver microsomes. 9,10-Dihydroxy-9,10,11,12-tetrahydrobenzo[e]pyrene, a compound which cannot be metabolized to a bay-region diol epoxide, was not metabolically activated to mutagenic metabolites in the presence or absence of 7,8-benzoflavone by any of the species examined. These results indicated that the effect of 7,8-benzoflavone on the enhanced mutagenic activity of benzo[e]pyrene 9,10-dihydrodiol is mediated by bay-region diol epoxides, which is consistent with the metabolism studies.

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PubMed1981

Tumorigenicity of the diastereomeric bay-region benzo(e)pyrene 9,10-diol-11,12-epoxides in newborn mice.

The tumorigenic activities of benzo(e)pyrene, 9,10-dihydrobenzo(e)pyrene, 9,10-epoxy-9,10,11,12-tetrahydrobenzo(e)-pyrene, the diastereomeric bay-region 9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrenes, and the K-region benzo(e)pyrene 4,5-oxide were assessed in newborn mice, Swiss-Webster mice received a total dose of 0.7 mumol of compound divided into three i.p. injections of 0.1, 0.2, and 0.4 mumol on the first, eighth, and 15th days of life, respectively. 9,10-Epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene was highly toxic to the newborn mice, and the first injection of 0.1 mumol of this benzo(e)pyrene derivative killed all the mice within two weeks. The total dose of 9,10-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene was therefore reduced to 0.07 mumol in divided doses of 0.01, 0.02, and 0.04 mumol. When the animals were killed at 39 to 43 weeks of age, one of the diastereomeric bay-region diol-epoxides, (+/-)-9 beta, 10 alpha-dihydroxy-11 beta, 12 beta-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene, produced a small but significant increase in pulmonary tumors in male mice but had no significant hepatotumorigenic activity. The diastereomerically related diol-epoxide. (+/-)-9 beta, 10 alpha-dihydroxy-11 alpha, 12 alpha-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene, produced a significant incidence of hepatic tumors but had no effect on the formation of pulmonary tumors. Benzo(e)pyrene and the other benzo(e)pyrene derivatives were all nontumorigenic at the doses tested.

Animals↗
PubMed1980

An enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (-)-benzo[a]pyrene 7,8-oxide.

The (+)- and (-)-enantiomers of benzo[a]pyrene 7,8-oxide are hydrated stereospecifically at C-8 to (-)- and (+)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, respectively, by rat hepatic epoxide hydrolase. The (-)-enantiomer of benzo[a]pyrene 7,8-oxide is metabolized by microsomal epoxide hydrolase at a rate 3- to 4-fold greater than the (+)-enantiomer. At low conversion of racemic substrate, however, benzo[a]pyrene 7,8-oxide is metabolized to the dihydrodiol at a rate equal to that of the (+)-enantiomer. An analysis of the enantiomeric composition of the dihydrodiol formed from the racemic substrate revealed preferential formation of (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo-[a]pyrene. At low substrate conversion (< 20% metabolism), the enantiomeric purity of the dihydrodiol was much higher than at high substrate conversion (> 50% metabolism). Similar results were obtained with microsomes from hamster, rabbit, guinea pig, mouse, and human liver. These results indicate that epoxide hydrolase has a higher affinity for (+)-benzo[a]pyrene 7,8-oxide than for the (-)-enantiomer. The kinetics of hydration of (+)- and (-)-benzo[a]pyrene 7,8-oxide by purified epoxide hydrolase in detergent solution showed the (+)- and (-)-enantiomers to have apparent Km values of 1.7 and greater than or equal to 20 microM, respectively. Tumorigenicity studies with benzo[a]pyrene 7,8-oxide on mouse skin and in newborn mice revealed that (+)-benzo[a]pyrene 7,8-oxide, the metabolic precursor of the more tumorigenic (-)-7,8-dihydrodiol, is significantly more tumorigenic than the (-)-enantiomer. However, racemic benzo[a]pyrene 7,8-oxide was more tumorigenic than either enantiomer alone, indicating an enantiomeric synergism in the carcinogenicity of benzo[a]pyrene 7,8-oxide. The data are discussed in relation to the complete sequence of metabolic pathways leading to an ultimate carcinogen from benzo[a]pyrene.

Animals↗
PubMed1980

Tumorigenic activity of benzo(e)pyrene derivatives on mouse skin and in newborn mice.

The tumorigenic activities of benzo(e)pyrene and several of its derivatives were determined in two mouse tumor models. Newborn Swiss-Webster mice were given i.p. injections of 0.4, 0.8, and 1.6 mumol of compound on the first, eighth, and 15th day of life, respectively. When the mice were 62 to 66 weeks old, the experiment was terminated by killing the animals. Benzo(e)pyrene, trans-4,5-dihydroxy-4,5-dihydrobenzo(e)pyrene, and trans-9,10-dihydroxy-9,10-dihydrobenzo(e)pyrene had little or no tumorigenic activity in lung tissue, although trans-9,10-dihydroxy-9,10-dihydrobenzo(e) pyrene did induce a significant number of hepatic tumors. The tumor-initiating activities of benzo(e)pyrene and several of its derivatives were determined on the skin of female CD-1 mice. A single topical application of 1.0 to 6.0 mumol of the test compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 35 weeks. Control mice and mice treated with 6.0 mumol of benzo(e)pyrene, trans-4,5-dihydroxy-4,5-dihydrobenzo(e)pyrene, trans 9,10-dihydroxy-9,10-dihydrobenzo(e)pyrene, and trans-9,10-dihydroxy-9,10,11,12-tetrahydrobenzo(e)pyrene had a tumor incidence of less than 20% and had less than or equal to 0.25 papillomas/mouse. 9,10-Dihydrobenzo(e)pyrene was the only derivative tested that had significant tumor-initiating activity on mouse skin; an initiating dose of 2.5 mumol gave a 67% tumor incidence and 1.43 papillomas/mouse.

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