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Biomedical subjects

H Yagi

Publications and source records attributed to H Yagi.

At least 343 records · Page 19Linked to original sources
PubMed1980

Mutagenicity and tumor-initiating activity of cyclopenta(c,d)pyrene and structurally related compounds.

The biological activities of benzo(a)pyrene, cyclopenta(c,d)pyrene, and 12 other structurally related compounds were assessed by mutagenicity studies with bacterial and mammalian cells and/or skin tumorigenicity studies with mice. The ability of the parent hydrocarbons to be metabolically activated to mutagenic products was examined in strains TA98 and TA100 of Salmonella typhimurium, using 3 experimental protocols. In each case, cyclopenta(c,d)pyrene was metabolically activated to products mutagenic to the bacteria to a greater extent than was benzo(a)pyrene. However, 7,8-dihydrobenzo(a)pyrene and 0,10-dihydrobenzo(e)pyrene were the best substrates for metabolic activation to bacterial mutagens. Highly purified epoxide hydrase added to a purified and reconstituted monooxygenase system readily abolished the mutagenic activity observed in strain TA100 of S. typhimurium when cyclopenta(c,d)pyrene was the substrate, but not when benzo(a)pyrene was the substrate. Inherent mutagenicity of several epoxides of the hydrocarbons generally paralleled the ability of their potential metabolic precursors to be activated to mutagens. 1-Pyrenyloxirane and 10,11-dihydrocycloheptapyrene 8,9-oxide were highly mutagenic in strains TA98 and TA100 of S. typhimurium, and in the former strain these activities were comparable to that observed with 9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, 4-Pyrenyloxirane was significantly less mutagenic than was 1-pyrenyloxirane in both strains of bacteria and in mammalian cells. Benzo(a)pyrene was over 20 times more tumorigenic than was cyclopenta-(c,d)pyrene, and it was the most potent of the 11 compounds tested for tumor-initiating activity in 2-stage initiation-promotion experiments on the skin of mice. Cyclopenta(c,d)pyrene had tumor-initiating activity comparable to that of benzo-(a)anthracene, but it was significantly less active than chrysene. Thus, contrary to inferences made from its high mutagenic activity, cyclopenta(c,d)pyrene is a weak tumor initiator on mouse skin.

Animals↗
PubMed1979

Absolute stereochemistry of the trans-dihydrodiols formed from benzo[a]anthracene by liver microsomes.

Through application of the exciton chirality method, absolute stereochemistry has been assigned to the (+)-and (-)-enantiomers of four of the five metabolically possible trans-dihydrodiols of the polycyclic hydrocarbon benzo[a]anthracene (BA). The (+)- and (-)-enantiomers of each of these dihydrodiols can be separated as their diastereomeric bis-esters with (-)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid by high pressure liquid chromatography (HPLC). BA 3,4-, 5,6-, 8,9- and 10,11-dihydrodiol are formed in 38%, 36%, 78% and 66% enantiometric purity, respectively, by liver microsomes from phenobarbital-treated rats, whereas the liver microsomes from 3-methylcholanthrene(MC)-treated rats form BA 5,6-, 8,9- and 10,11-dihydrodiols with higher optical purity (62%, 96% and 96%, respectively). BA 3,4-dihydrodiol is formed from (+/-)-BA 3,4-oxide by microsomal epoxide hydrase in very high enantiometric purity (78%). The major enantiomer of the BA dihydrodiols formed by liver enzymes has R,R absolute stereochemistry in each case. In parallel with previous studies on the metabolism of benzo[a]pyrene, the more tumorigenic (-)-enantiomer is the predominant isomer of BA 3,4-dihydrodiol formed by liver microsomes from BA.

Animals↗
PubMed1979

[Clinical significance of urinary CEA measurement as a screening test of bladder cancer (author's transl)].

Non-infected urine samples of twenty six preoperative bladder cancers were examined by urinary CEA radioimmunoassay and exfoliative cytology. There were 65% of urinary CEA positivity and 58% of cytological positivity (class III, IV, V). CEA measurements were positive in 8 of 11 negative cytology cases (class I and II). Exfoliative cytological examination failed to detect most of well differentiated transitional cell carcinomas, while urinary CEA study detected 4 of 6 such cases. Combination of both urinary CEA measurement and cytology resulted in 85% of positivity. Therefore we recommend routine use of this combination as a screening system of bladder cancer.

Adult↗
PubMed1979

Neoplastic effects of oral administration of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and their inhibition by butylated hydroxyanisole.

The neoplastic effects of administration of benzo[a]pyrene (BP) and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP 7,8-dihydrodiol) by oral intubation to noninbred female Ha:ICR mice have been determined. Under the experimental conditions, BP induced papillomas of the forestomach. BP 7,8-dihydrodiol also induced papillomas of the forestomach and was more potent than BP. In addition, administration of BP 7,8-dihydrodiol caused a large number of pulmonary adenomas and lymphomas. Butylated hydroxyanisole (BHA) added to the diet at a concentration of 5 mg/g inhibited BP-induced neoplasia of the forestomach. BHA also inhibited neoplasia of the forestomach, lungs, and lymphoid tissues that was caused by administration of BP 7,8-dihydrodiol. These data suggest that the inhibitory effect of BHA on BP carcinogenesis may entail events that occur subsequent to the formation of BP 7,8-dihydrodiol.

Adenoma↗
PubMed1979

Carcinogenicity of 2-hydroxybenzo(a)pyrene and 6-hydroxybenzo(a)pyrene in newborn mice.

Benzo(a)pyrene (BP), 2-hydroxybenzo(a)pyrene (2-HOBP), and 6-hydroxybenzo(a)pyrene (6-HOBP) were tested for tumorigenicity by i.p. injection into newborn mice. The mice were treated sequentially with 200, 400, and 800 nmol of compound on the first, eighth and fifteenth day of life, and the animals were killed at 24 weeks of age. Treatment with 2-HOBP caused about 4-fold more pulmonary tumors than BP, while 6-HOBP had little or no tumorigenic activity. Newborn mice treated with 2-HOBP, BP, and 6-HOBP had a 98, 81, and 11% incidence of pulmonary adenomas with an average of 24, 6.4, and 0.11 adenomas per mouse, respectively. In the control group, 7.5% of the animals had pulmonary adenomas with an average of 0.08 adenoma per mouse. When 25, 50, or 100 nmol of BP or 2-HOBP was applied to mouse skin once every 2 weeks for 60 weeks, both compounds had about the same carcinogenic activity. These results demonstrate the importance of evaluating the carcinogenic potential of chemicals in more than one tumor system. BP and 2-HOBP were tested for mutagenicity towards two strains of Salmonella typhimurium and towards Chinese hamster V79 cells in the presence of hepatic microsomes from rats pretreated with Aroclor 1254. The products formed during the metabolism of 2-HOBP or BP by liver microsomes had significant mutagenic activity.

Adenoma↗
PubMed1978

Binding of benzo[a]pyrene 7,8-diol-9,10-epoxides to DNA, RNA, and protein of mouse skin occurs with high stereoselectivity.

The formation, stereostructure, and cellular reactions of the 7,8-diol-9,10-epoxide metabolites of the carcinogen benzo[a]pyrene have been examined after topical application of benzo[a]pyrene to the skin of mice. In this known target tissue, polymer adducts from diastereomeric diol epoxides, (+)-(7S, 8R, 9R, 10R) and (+)-(7R, 8S, 9R, 10R), were formed stereospecifically from their corresponding 7,8-dihydrodiols. Both diol epoxides bind with proteins, RNA, and DNA in vivo. For the nucleic acids, binding occurs preferentially at the 2-amino group of guanine in cellular RNA and DNA in vivo. Methods for establishing the structure of the cellular adducts as well as the possible biological implications of their formation are discussed.

Animals↗
PubMed1978

Repair of DNA damaged by mutagenic metabolites of benzo(a)pyrene in human cells.

The repair of human DNA after damage by known and potential metabolites of benzo(a)pyrene has been examined utilizing the bromodeoxyuridine photolysis assay. Repair was characterized as either ultraviolet ("long") or ionizing radiation type ("short") repair utilizing normal cells and cells deficient in ultraviolet-type repair endonuclease from a patient with xeroderma pigmentosum (XP). We have found that only (+/-)-7beta,8alpha-dihydroxy-9beta,-10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP diol epoxide 1) and its disastereomer, (+/-)-7beta,8alpha,-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP diol epoxide 2) elicit damage to DNA which is recognizable by the ultraviolet excision repair system in normal human cells. Benzo(a)pyrene 4,5-, 9,10-, 11,12-oxides do not elicit damage which is repairable by this repair system. The 1,2-diol-3,4-epoxides from naphthalene have no measurable activity in our assay. These results indicate that both the benzo(a)pyrene ring structure and the diol epoxide groups are important in causing the damage to DNA which is repairable by the ultraviolet excision repair system. These results parallel the reported high mutagenic activity of these compounds and support the concept that benzo(a)pyrene 7,8-diol-9,10-epoxides may be the ultimate, metabolically activated forms of benzo(a)pyrene.

Benzopyrenes↗
PubMed1978

Postreplication repair of DNA in human fibroblasts after UV irradiation or treatment with metabolites of benzo(a)pyrene.

We have examined the ability of normal fibroblasts and of excision-deficient xeroderma pigmentosum (XP) and XP variant fibroblasts to perform postreplication DNA repair after increasing doses of either ultraviolet (UV) irradiation or mutagenic benzo(a)pyrene derivatives. XP cells defective in the excision of both UV-induced pyrimidine dimers and guanine adducts induced by treatment with the 7,8-diol-9,10-epoxides of benzo(a)pyrene were partially defective in their ability to synthesize high molecular weight DNA after the induction of both classes of DNA lesions. This defect was more marked in XP variant cells, despite their ability to remove by excision repair both pyrimidine dimers and the diol epoxide-induced lesions to the same degree as observed in normal cells. The benzo(a)pyrene 9,10-oxide had no effect in any of the 3 cell lines. The response of the excision and postreplication DNA repair mechanisms operating in human fibroblasts treated with benzo(a)pyrene 7,8-diol-9,10-epoxides, therefore, appears to resemble closely that seen after the induction of pyrimidine dimers by UV irradiation.

Benzopyrenes↗