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Biomedical subjects

H Yagi

Publications and source records attributed to H Yagi.

At least 307 records · Page 17Linked to original sources
PubMed1984

Tumorigenicity of dihydrodiols and diol-epoxides of benz[c]acridine in newborn mice.

The tumorigenicity of benz[c]acridine (B[c]ACR) and a number of its derivatives, including the five metabolically possible transdihydrodiols, the diastereomeric bay-region diol-epoxides, two non-bay-region diol-epoxides, and the K-region 5,6-oxide, were assessed in newborn mice. A total dose of 0.50 or 1.05 mumol of compound was administered i.p. to preweanling mice, and tumorigenic activity was determined when the mice were 33 to 37 weeks old. B[c]ACR was a weak carcinogen producing an average of 2.5 lung tumors/mouse and 0.15 liver tumor/male mouse at the 1.05-mumol dose. Of the five metabolically possible trans-dihydrodiols of B[c]ACR, only trans-3,4-dihydroxy-3,4-dihydro-B[c] ACR (B[c]ACR (B[c]ACR 3,4-dihydrodiol) had high tumorigenic activity. B[c]ACR 3,4-dihydrodiol induced 2- and 10-fold more pulmonary and hepatic tumors, respectively, than did the parent compound while the trans-1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols had very little or no tumorigenic activity. Both of the diastereomeric bay-region 3,4-diol-1,2-epoxides, in which the epoxide oxygen is either cis (isomer 1) or trans (isomer 2) to the benzylic hydroxyl group, had tumorigenic activity. Isomer 2 was the most tumorigenic derivative tested, inducing at least 60, 7, and 12 times more lung tumors per mouse than did isomer 1, B[c]ACR 3,4-dihydrodiol and B[c]ACR, respectively. The K-region 5,6-oxide and two non-bay-region diol-epoxides (isomer 2 of B[c]ACR 8,9-diol-10,11-epoxide and B[c]ACR 10,11-diol-8,9-epoxide) were weakly active or inactive at the dose tested. The demonstration that B[c]ACR 3,4-diol-1,2-epoxide-2 is exceptionally tumorigenic and that its metabolic precursor, B[c]ACR 3,4-dihydrodiol, is more active than the parent hydrocarbon, B[c]ACR, support the concept that isomer 2 of the bay-region diol-epoxide may be an ultimate carcinogenic metabolite of B[c]ACR.

Acridines↗
PubMed1984

High stereoselectivity among the optical isomers of the diastereomeric bay-region diol-epoxides of benz(a)anthracene in the expression of tumorigenic activity in murine tumor models.

The tumorigenicity of the (+)- and (-)-enantiomers of the diastereomeric bay-region benz(a)anthracene 3,4-diol-1,2-epoxides was evaluated in two mouse tumor models. In an initiation-promotion experiment on mouse skin, a single topical application of 0.1 or 0.4 mumol of the benz(a)anthracene diol-epoxides was followed by 25 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Of the four isomers of the bay-region diol-epoxides, only (+)-[1R,2S,3S,4R]-3,4-dihydroxy-1,2-epoxy-1,2,3,4- tetrahydrobenz(a)anthracene [(+)-diol-epoxide-2] and (+)-[1R,2S,3S,4S]-3,4-dihydroxy-1,2-epoxy-1,2,3,4- tetrahydrobenz(a)anthracene [(+)-diol-epoxide-1] had significant tumor-initiating activity. (+)-Diol-epoxide-2 was approximately 4-fold more active as a tumor initiator on mouse skin than was (+)-diolepoxide-1 at both doses tested. In newborn mice, a total of 0.14 mumol of compound, divided into three doses, was administered i.p. on the first, eighth, and fifteenth day of life, and tumorigenic activity was determined when the mice were 26 to 32 weeks of age. As was observed in the initiation-promotion experiment on mouse skin, only two of the four optical isomers of the bay-region diol-epoxides produced a significant tumor incidence. (+)-Diol-epoxide-2 induced a 100% incidence of lung tumors, with an average of 23.11 tumors/mouse, and was at least 60-fold more active (average number of tumors per mouse) than was (+)-diol-epoxide-1, which produced a 31% lung tumor incidence and 0.38 lung tumors/mouse. (+)-Diol-epoxide-2 was the only optical isomer that induced a significant incidence of hepatic tumors in male mice (31% incidence, 1.17 tumors/mouse). The highly tumorigenic (+)-diol-epoxide-2 isomer with [R,S,S,R] absolute configuration has the same absolute configuration as does the highly tumorigenic isomer of the bay-region diol-epoxides of benzo(a)pyrene and chrysene.

Animals↗
PubMed1983

Inhibition of the mutagenicity of bay-region diol-epoxides of polycyclic aromatic hydrocarbons by phenolic plant flavonoids.

Myricetin, robinetin and luteolin inhibited the mutagenic activity resulting from the metabolic activation of benzo[a]-pyrene and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene by rat liver microsomes. These naturally occurring plant flavonoids and seventeen additional flavonoids and related derivatives with phenolic hydroxyl groups inhibited the mutagenic activity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), which is an ultimate mutagenic and carcinogenic metabolite of benzo[a]pyrene. Several flavonoids without phenolic hydroxyl groups or with methylated phenolic hydroxyl groups were inactive. The mutagenic activity of 0.05 nmol of BP 7,8-diol-9,10-epoxide-2 towards strain TA 100 of S. typhimurium was inhibited 50% by incubation of the bacteria and the diol-epoxide with myricetin (2 nmol), robinetin (2.5 nmol), luteolin (5 nmol), quercetin (5 nmol), 7-methoxyquercetin (5 nmol), rutin (5 nmol), quercetin (5 nmol), delphinidin chloride (5 nmol), morin (10 nmol), myricitrin (10 nmol), kaempferol (10 nmol), diosmetin (10 nmol), fisetin (10 nmol), or apigenin (10 nmol). Considerably less antimutagenic activity was observed for dihydroquercetin, naringenin, robinin, D-catechin, genistein, kaempferide and chrysin. Pentamethoxyquercetin, tangeretin, nobiletin, 7,8-benzoflavone, 5,6-benzoflavone, and flavone, which lack free phenolic groups, were inactive. The antimutagenic activity of hydroxylated flavonoids results from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2 since the rate of disappearance of the diol-epoxide from cell-free solutions in 1:9 dioxane:water was markedly stimulated by myricetin, robinetin and quercetin. Myricetin was a highly potent inhibitor of the mutagenic activity of bay-region diol-epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene and dibenzo[a,i]pyrene, but higher concentrations of myricetin were needed to inhibit the mutagenicity of the chemically less reactive benzo[a]pyrene 4,5-oxide and bay region diol-epoxides of benz[a]anthracene, chrysene and benzo[c]phenanthrene.

Animals↗
PubMed1983

Mutagenicity of the enantiomers of the diastereomeric bay-region benz(a)anthracene 3,4-diol-1,2-epoxides in bacterial and mammalian cells.

Enantiomers of the diastereomeric pair of bay-region benz(a)anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity in two histidine-dependent strains of Salmonella typhimurium, as well as in an 8-azaguanine-sensitive Chinese hamster cell line. In strain TA 98 of S. typhimurium, the diol-epoxide with (1S,2R,3R,4S) absolute configuration [(-)-diol-epoxide 2] was the most active isomer, although there was less than a 3-fold difference in the mutagenicity of the four diol-epoxides. However, in strain TA 100 of S. typhimurium, the enantiomeric diol-epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol-epoxide 2] was the most active diol-epoxide, and the two isomers with (3S,4R) absolute configuration [(-)-diol-epoxide 1 and (+)-diol-epoxide 2] were three to eight times more active than were the two isomers with (3R,4S) configuration. The highest degree of sensitivity to absolute configuration was observed in Chinese hamster V79 cells, in which the (1R,2S,3S,4R) isomer [(+)-diol-epoxide 2] was from three to 20 times more mutagenic than were the other three isomers. This metabolically predominant (+)-diol-epoxide 2 isomer, which has high activity in strain TA 100 of S. typhimurium and the Chinese hamster V79 cells, has the same absolute configuration as do the bay-region diol-epoxide isomers of benzo(a)pyrene and chrysene that have been shown previously to be exceptionally mutagenic to mammalian cells and highly tumorigenic in mice. Analysis of the mutagenic activity of the (+)- and (-)-isomers of the 1,2- and 3,4-tetrahydroepoxides of benz(a)anthracene revealed only small enantiomeric differences in strain TA 98 of S. typhimurium (2.5 fold) and little, if any, differences (less than 1.5-fold) in the other two mutagenicity systems. However, the extent to which the four tetrahydroepoxides were converted to nonmutagenic products by homogeneous microsomal epoxide hydrolase (EC 3.3.2.3) indicated marked differences in the stereoselectivity of the enzyme. (-)-(3R,4S)-Epoxy-1,2,3,4-tetrahydrobenz(a)anthracene appears to be an exceptionally good substrate for epoxide hydrolase.

Animals↗
PubMed1983

Regioselectivity and stereoselectivity in the metabolism of trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene by rat liver microsomes.

Metabolism of [3H]-(+/-)-trans-1,2-dihydroxy-1,2-dihydrobenz[a] anthracene by liver microsomes isolated from control, phenobarbital-treated, and 3-methylcholanthrene-treated Long-Evans rats and from 3-methylcholanthrene-treated Sprague-Dawley rats was examined. Liver microsomes from both control and phenobarbital-treated rats metabolized the dihydrodiol at a rate of 0.5 nmol/nmole of cytochrome P450 per minute, whereas prior treatment of rats with 3-methylcholanthrene stimulated the rate of metabolism by 4-fold. Prior treatment of the rats caused marked differences in the regio- and stereoselectivity of the metabolism of this pseudo-diaxial dihydrodiol. In each case, the major metabolites were three bis-dihydrodiols and a pair of diastereomeric 1,2-diol-3,4-epoxides in which the benzylic 1-hydroxyl group is either cis or trans to the epoxide oxygen (diol epoxides-1 and -2, respectively). The presence of the diol epoxides in the incubation medium was inferred from the identification of their corresponding tetraols, which arise by hydrolysis of the diol epoxides on chromatography. Hepatic microsomes from control and phenobarbital-treated rats metabolized the 1,2-dihydrodiol predominantly to 1,2-diol-3,4-epoxides (68-85% of the total metabolites) whereas bis-dihydrodiols represented 28% and 13% of the total metabolites, respectively. In contrast, liver microsomes from 3-methylcholanthrene-treated rats of either strain metabolized the 1,2-dihydrodiol primarily to isomeric bis-dihydrodiols (51-56% of total metabolites), with diol epoxides accounting for only 36-38% of the total metabolites. Bis-dihydrodiol-1 (32-35% of the total metabolites) was formed in greater amounts (2- to 4-fold) than either bis-dihydrodiols-2 or -3, which were formed in about equal amounts and have identical absorption spectra. The ratio of the diastereomeric 1,2-diol-3,4-epoxides-1 and -2 was highly dependent upon the preparation used. For microsomes from control and phenobarbital-treated rats, this ratio was between 3:1 and 4:1 whereas microsomes from 3-methylcholanthrene-treated rats (greater than 70% cytochrome P-450c) gave a ratio of between 1:1.5 and 1:2. The basis for this ratio in the latter case was explained by examination of the products formed from the (+)-(1S,2S)-and (-)-(1R,2R)-enantiomers of the dihydrodiol on metabolism by a highly purified system reconstituted with cytochrome P-450c. The (-)-isomer is a 3-fold better substrate than the (+)-isomer and forms only the diol epoxide-2 diastereomer, whereas the (+)-isomer forms much more diol epoxide-1 than diol epoxide-2 diastereomer.

Animals↗
PubMed1983

Tumor-initiating activity of benz[c]acridine and twelve of its derivatives on mouse skin.

Benz[c]acridine (B[c]ACR) and 12 of its derivatives, including the 5 metabolically possible trans-dihydrodiols, the diastereomeric bay-region diol-epoxides, 2 non-bay-region diol-epoxides, and the K-region arene oxide, were tested for tumor-initiating activity on mouse skin. A single topical application of 0.4 to 2.5 mumol of compound was followed 12 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. B[c]ACR was a weak tumor initiator on mouse skin, producing a 37% tumor incidence and 1.33 tumors/mouse at the 2.5-mumol dose. Of the five metabolically possible trans-dihydrodiols of B[c]ACR, only trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR had significant tumor-initiating activity. This compound was at least 6-fold more active than was the parent compound at the three doses tested. The diastereomeric bay-region diol-epoxides, in which the epoxide oxygen is either cis(isomer 1) or trans (isomer 2) to the benzylic hydroxyl group, each had significant tumor-initiating activity, although isomer 2 was at least 5-fold more active than was isomer 1 and had activity equal to that of its potential metabolic precursor, trans-3,4-dihydroxy-3,4-dihydro-B[c]ACR. Two non-bay-region diol-epoxides (isomer 2 of the 8,9-diol-10,11-epoxide and the 10,11-diol-8,9-epoxide) and the 5,6-arene oxide (K-region) were inactive at the doses tested. 3,4-Dihydro-B[c]ACR, the potential metabolic precursor of a bay-region tetrahydroepoxide, was the most potent tumor initiator analyzed in the present study. At an initiating dose of 0.4 mumol, this compound produced a 97% tumor incidence and 7.90 tumors/mouse after 15 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. These results suggest that B[c]ACR, the N-12 analogue of benz[a]anthracene, undergoes metabolic activation to an ultimate carcinogenic metabolite via formation of a bay-region diol-epoxide, as has already been demonstrated for benz[a]anthracene.

Acridines↗
PubMed1982

Mechanism of the inhibition of mutagenicity of a benzo[a]pyrene 7,8-diol 9,10-epoxide by riboflavin 5'-phosphate.

Riboflavin 5'-phosphate (flavin mononucleotide; FMN) inhibits the mutagenicity of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P diol epoxide), the only known ultimate carcinogenic metabolite of benzo[a]pyrene. Coincubation of 10, 25, and 50 nmol of FMN with strain TA100 of histidine-dependent Salmonella typhimurium inhibits the mutagenicity of 0.05 nmol of the diol epoxide by 50, 70, and 90%, respectively. Ribose 5-phosphate and riboflavin show no significant effects at comparable doses. Reaction of B[a]P diol epoxide with FMN in aqueous solution at neutral pH produces only tetraols, with no evidence for covalent adducts. At pH 7 the rate of hydrolysis of B[a]P diol epoxide in dioxane/water, 1:9 (vol/vol), at 25 degrees C is increased more than 10-fold in the presence of 100 muM FMN. Spectrophotometric studies and quantitative rate data for the reaction of the diol epoxide with FMN indicate that a complex is formed between the diol epoxide and the flavin moiety of FMN (Ke = 1,400-3,400 M-1) prior to general acid-catalyzed hydrolysis of the epoxide to tetraols by the phosphate monoanion of FMN. Comparable concentrations of ribose 5-phosphate and riboflavin do not significantly increase the rate of hydrolysis, although evidence for complex formation between riboflavin and the diol epoxide is observed. General acid-catalyzed hydrolysis of bay-region polycyclic hydrocarbon diol epoxides by compounds that have a high affinity for these ultimate carcinogens represents a potentially useful way of inhibiting their carcinogenic activity.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1982

Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols: exceptional activity of ellagic acid.

Ferulic, caffeic, chlorogenic, and ellagic acids, four naturally occurring plant phenols, inhibit the mutagenicity and cytotoxicity of (+/-)-7beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), the only known ultimate carcinogenic metabolite of benzo[a]pyrene. The mutagenicity of 0.05 nmol of B[a]P 7,8-diol-9,10-epoxide-2 in strain TA100 of Salmonella typhimurium is inhibited 50% by incubation of the bacteria and the diol epoxide with 150 nmol of ferulic acid, 75 nmol of caffeic acid, 50 nmol of chlorogenic acid or, most strikingly, 1 nmol of ellagic acid in the 0.5-ml incubation mixture. A 3-nmol dose of ellagic acid inhibits mutation induction by 90%. Ellagic acid is also a potent antagonist of B[a]P 7,8-diol-9,10-epoxide-2 in Chinese hamster V79 cells. Mutations to 8-azaguanine resistance induced by 0.2 muM diol epoxide are reduced by 50% when tissue culture media also contains 2 muM ellagic acid. Similar to results obtained with the bacteria, ferulic, caffeic, and chlorogenic acids are approximately two orders of magnitude less active than ellagic acid in the mammalian cell assay. The antimutagenic effects of the plant phenols result from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2, because a concentration-dependent increase in the rate of diol epoxide disappearance in cell-free solutions of 1:9 dioxane/water, pH 7.0, is observed with all four phenols. In parallel with the mutagenicity studies, ellagic acid is 80-300 times more effective than the other phenols in accelerating the disappearance of B[a]P 7,8-diol-9,10-epoxide-2. Ellagic acid at 10 muM increases the disappearance of B[a]P 7,8-diol-9,10-epoxide-2 by approximately 20-fold relative to the spontaneous and hydronium ion-catalyzed hydrolysis of the diol epoxide at pH 7.0. Ellagic acid is a highly potent inhibitor of the mutagenic activity of bay-region diol epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene, and dibenzo[a,i]pyrene, but higher concentrations of ellagic acid are needed to inhibit the mutagenic activity of the chemically less reactive bay-region diol epoxides of benz[a]anthracene, chrysene, and benzo[c]phenanthrene. These studies demonstrate that ellagic acid is a potent antagonist of the adverse biological effects of the ultimate carcinogenic metabolites of several polycyclic aromatic hydrocarbons and suggest that this naturally occurring plant phenol, normally ingested by humans, may inhibit the carcinogenicity of polycyclic aromatic hydrocarbons.

Animals↗
PubMed1982

Mutagenicity of the optical isomers of the diastereomeric bay-region chrysene 1,3-diol-3,4-epoxides in bacterial and mammalian cells.

The mutagenic activities of the four optically pure (+)- and (-)-enantiomers of the two diastereomeric bay-region chrysene 1,2-diol-3,4-epoxides were evaluated in histidine-dependent strains of Salmonella typhimurium and in cultured Chinese hamster V79 cells. In strain TA98 of S. typhimurium, (-)-1 alpha, 2 beta-dihydroxy-3 beta, 4 beta-epoxy-1,2,3,4-tetrahydrochrysene was 5 to 10 times more active than the other three optical isomers. However, in strain TA100 of S. typhimurium and in Chinese hamster V79 cells, (+)-1 beta, 2 alpha-dihydroxy-3 alpha, 4 alpha-epoxy-1,2,3,4-tetrahydrochrysene was the most mutagenic diol-epoxide and was from 5 to 40 times more active than the other three optical isomers. The bay-region (+)- and (-)-3,4-epoxy-1,2,3,4-tetrahydrochrysene isomers has identical mutagenic activities in all three systems. These studies indicate that the presence and orientation of the hydroxyl groups play an important role in modulating the mutagenic activity of bay-region epoxides of chrysene in both bacterial and mammalian cells.

Animals↗