Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,8- and 7,8-diol-9,10-epoxides and 7,8-diol

Slaga, Thomas J.; Viaje, Aurora; Berry, David L.; Bracken, William M.; Buty, S. G.; Scribner, John D.

doi:10.1016/s0304-3835(76)80020-1

Cited by 99 publications

(23 citation statements)

References 20 publications

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“…as the primary carcinogenic metabolite of BP exhibiting enhanced mutagenic activity in vitro and in vivo (13)(14)(15)(16)(17). Most previous studies of genetic variation in metabolism of lung carcinogens have focused on metabolic activation by various CYPs, although expression of these enzymes in lung is generally low (18).…”

Section: -Tetrahydro-bp [(+)-Anti-bpde] Is Formed From Bp By Two Romentioning

confidence: 99%

DNA Damage by Benzo(a)pyrene in Human Cells Is Increased by Cigarette Smoke and Decreased by a Filter Containing Rosemary Extract, Which Lowers Free Radicals

Alexandrov

Rojas²,

Rolando³

2006

Cancer Research

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We found previously that the human lung benzo(a)pyrene (BP)-7,8-diol-9,10-epoxide-N 2 -deoxyguanosine (BPDE-dG) adduct concentrate in the target bronchial cells. This adduct is now considered to be critical event in tumorigenesis by BP. In this study, we investigate the contribution of cigarette smoke on the BPDE-dG formation. In a cell-free system, the amount of (À)-anti-BPDE-dG adduct increased linearly with concentration of cigarette smoke in the presence of (+)-BP-7,8-diol. Catalase and superoxide dismutase inhibited its formation by >80%. When MCF-7 cells were treated for 2 hours with the (+)-BP-7,8-diol, cigarette smoke increased dose dependently the formation of (À)-anti-BPDE-dG and decreased the cytochrome P450 (CYP)-dependent formation of (+)-r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydro-BP the adduct. Then, cells were treated for up to 1 day with BP and then exposed for 2 hours with cigarette smoke. During these 2 hours, there are twice the increase in the adduct formation in cells treated with cigarette smoke compared with levels in nontreated cells due to CYP activity. Thus, cigarette smoke containing reactive oxygen species may activate the second step of BP metabolic way, leading to the formation of BPDE-dG adduct. Cigarette smoke thus seems may be in part responsible for the formation of the critical lung tumorigenic adduct. Finally, modified cigarette filter containing rosemary extract decreases by >70% of the BPDE-dG adducts level due to the cigarette smoke in MCF-7 cells. This approach may lead to decreasing lung cancer risk in addicted smokers. (Cancer Res 2006; 66(24): 11938-45)

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Section: -Tetrahydro-bp [(+)-Anti-bpde] Is Formed From Bp By Two Romentioning

confidence: 99%

DNA Damage by Benzo(a)pyrene in Human Cells Is Increased by Cigarette Smoke and Decreased by a Filter Containing Rosemary Extract, Which Lowers Free Radicals

Alexandrov

Rojas²,

Rolando³

2006

Cancer Research

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“…The latter metabolites possess high chemical (11,12) and mutagenic (6,(13)(14)(15) activity, are potent inducers of epidermal hyperplasia (16), and interact with nucleophilic sites on cellular DNA, RNA, and protein (4,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) (27,28). Although the diastereomeric BP-7,8-diol-9,10-epoxides are less carcinogenic than BP on mouse skin (29,30), dihydrodiol is a potent carcinogen with activity comparable to or somewhat greater than BP (29,31,32 (33). The structures of these four isomers of the BP-7,8-diol-9,10-epoxides are shown in Fig.…”

mentioning

confidence: 99%

Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Buening

Wislocki

Levin

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

370

152

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The tumorigenicities of benzo[a]pyrene and each optical enantiomer of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides derived from trans-7,8-dihydroxy-7,8-dihydrobenzol[a]pyrene were tested by sequential intraperitoneal injection of mice with 1,2, and 4 nmol, or with 2, 4, and 8 nmol of each compound on the 1st, 8th, and 15th day of life, respectively. The experiment was terminated when the animals were 34--37 weeks old. (+)-7beta, 8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzol[a]pyrene [(+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2] had exceptional tumorigenicity, whereas benzo[a]-pyrene and the other three optically pure isomers of the benzo[a]pyrene 7,8-diol,9,10-epoxides had little or no activity. These results demonstrate differences in the carcinogenic activities of optically active isomers of a polycyclic hydrocarbon diol epoxide. Eleven percent of control mice had pulmonary tumors, whereas 71% and 100% of the mice treated with a total dose of 7 or 14 nmol of (+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2, respectively, had pulmonary tumors. Control mice had an average of 0.12 pulmonary tumors per mouse, whereas mice treated with a total dose of 7 or 14 nmol of (+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2 had 1.72 and 7.67 pulmonary tumors per mouse, respectively. Mice treated with 14 nmol of (-)-BP-7alpha,8beta-diol-9beta,10beta-epoxide 2, (-)-BP-7beta,8alpha-diol-9beta,10beta-epoxide 1, or (+)-BP-7alpha,8beta-diol-9alpha,10alpha-epoxide 1 had 0.13, 0.25, and 0.34 pulmonary tumors per animal, respectively.

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“…The postulated mechanisms for a possible increased risk of chemical carcinogenesis in cigarette smokers with high levels of AHH concern the production during metabolism and/or remetabolism of the polycyclic aromatic hydrocarbons in cigarette smoke to intermediate products of high mutagenic (6)(7)(8)(9)(10) and carcinogenic (11)(12) potential. In addition to differences in the generation of metabolites, another critical factor in determining susceptibility to carcinogens might be individual variation in the affinity of binding of these metabolites to DNA (24).…”

Section: Methodsmentioning

confidence: 99%

“…benzo(a)pyrene and benzo(a)-anthracene [BA]) into more polar, water-soluble compounds that are eliminated from the body. During hydroxylation, intermediate compounds with enhanced mutagenic (6)(7)(8)(9)(10) and carcinogenic (11,12) activities are formed. Large quantities of AHH may be harmful to cigarette smokers through increased production of these potent intermediate compounds from the polycyclic hydrocarbons present in cigarette smoke.…”

mentioning

confidence: 99%

Comparison of Aryl Hydrocarbon Hydroxylase Induction in Cultured Blood Lymphocytes and Pulmonary Macrophages

McLemore¹,

Martin²,

Toppell³

et al. 1977

J. Clin. Invest.

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A B S T R A C T Aryl hydrocarbon hydroxylase induction was studied in cultured peripheral blood lymphocytes and pulmonary alveolar macrophages from 15 smokers and 8 nonsmokers with a variety of pulmonary diseases. Enzyme levels in lymphocytes from cigarette smokers cultured in medium without an inducing agent were 57±6 mU/106 cells (mean+SEM), while enzyme levels in lymphocytes from nonsmokers were 20+2 mU/106 cells (P < 0.001). When lymphocytes were cultured in the presence of the inducing agent, benzo-(a)anthracene, enzyme activity was increased to 168 +23 mU/106 cells in smokers' cells and 99+22 mU/106 cells in lymphocytes from nonsmokers (P < 0.04).When noninduced enzyme values in cultured macrophages were compared, smokers' cells had enzyme levels of 45+5 mU/106 cells, whereas nonsmokers had enzyme activity of 24±2 mU/106 cells (P < 0.002). However, pulmonary macrophages from smokers or nonsmokers, cultured in the presence of benzo(a)-anthracene, had similar levels of induced enzyme activity (P > 0.1). A positive correlation was observed for nonsmokers (r = 0.596, P > 0.1 <0.2) or smokers (r = 0.640, P < 0.04), when enzyme values for noninduced cultures of macrophages and lymphocytes from individual patients were simultaneously compared. Enzyme values for macrophages and lymphocytes cultured in the presence of an inducer also revealed a positive correlation for individual smokers (r = 0.801, P < 0.001) or nonsmokers (r = 0.785, P < 0.01). Inducibility (expressed as fold-induction) for macrophages Dr positively correlated (r = 0.889, P < 0.001 for nonsmokers and r = 0.942, P < 0.001 for smokers). These results indicate that the capacity for aryl hydrocarbon hydroxylase induction is similar whether tested in lymphocytes or pulmonary macrophages from this group of pulmoniary disease patients.

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Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,8- and 7,8-diol-9,10-epoxides and 7,8-diol

Cited by 99 publications

References 20 publications

DNA Damage by Benzo(a)pyrene in Human Cells Is Increased by Cigarette Smoke and Decreased by a Filter Containing Rosemary Extract, Which Lowers Free Radicals

DNA Damage by Benzo(a)pyrene in Human Cells Is Increased by Cigarette Smoke and Decreased by a Filter Containing Rosemary Extract, Which Lowers Free Radicals

Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Comparison of Aryl Hydrocarbon Hydroxylase Induction in Cultured Blood Lymphocytes and Pulmonary Macrophages

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