Mutagenicity and Carcinogenicity of Benzo[a]pyrene and Benzo[a]pyrene Derivatives

Levin, Wayne; Wood, Alexander W.; Wislocki, Peter G.; Chang, Richard L.; Kapitulnik, Jaime; Mah, Heduck; Yagi, Haruhiko; Jerina, D. M.; Conney, Allan H.

doi:10.1016/b978-0-12-279201-4.50016-5

Cited by 50 publications

(35 citation statements)

References 29 publications

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“…An increased metabolism of xylene j'tself with an increased formation of p-tolualdeihyde from p-xylene can lead to the destruction of lung microsomal cytochrome P-450 after transport of the metabolite to the lung, as proposed by Patel et al (23). The increased formation of 4,5-dihydroxy-4,5~dihydrobenzo{a)py rene implies an accelerated formation of the mutagenrc 4,5-epoxy-4,5-dihydrobenzo-(a)pyrene (15). The toxicological importance of this metabolite may be questionable, however, in view of recent reports on the efficient deact'ivation of this compound by epoxide hydrase and glutathione-S-transferase (11,34).…”

Section: Discussionmentioning

confidence: 71%

“…The toxicological importance of this metabolite may be questionable, however, in view of recent reports on the efficient deact'ivation of this compound by epoxide hydrase and glutathione-S-transferase (11,34). In contrast further metabolism of 7,8-dVhydroxy-7,8-dihydrolbenzo(a)pyrene can lead to the formation of the very potent carc'inogen and mutagen 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo{a)pyrene (15). When animals given phenobarbital are exposed to n"':hexane, an increased formation of 2~hexanol occurs (9) and probably leads to an ac'celerated production of the neurotoxic metaJbolite 2,5-hexanedione.…”

Section: Discussionmentioning

confidence: 99%

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Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks.

Toftgárd¹,

Nilsen²,

Gustafsson

1981

Scand J Work Environ Health

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Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks. by Toftgård R, Nilsen OG, Gustafsson J-A Key terms: benzo(a)pyrene metabololism; enzymatic activity; induction; inhalation; methyl ethyl ketone; methylchloroform; microsomal cytochrome P-450; n-hexane; organic solvent; rat; rat liver; rat liver microsomal cytochrome P-450; steroid metabolism; xylene This article in PubMed: www.ncbi.nlm.nih.gov/pubmed/7313607Scand j work environ health 7 (1981) [31][32][33][34][35][36][37] Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks by Rune Toftgard, SSe," 2 Odd G Nilsen, PhD,1.3 Jan-Ake Gustafsson MD, PhD 2 TOFTGARD R, NILSEN OG, GUSTAFSSON J-A. Changes in rat liver microsomal cytochrome P-450 and enzymatic activities afber the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for :flour weeks. Scand j work environ health 7 (1981) 31-37. Groups of Sprague-Dawley rats were exposed, by inhalation, to n-hexane (900 ppm, 3,240 mg/m3), xylene (600 ppm, 2,625 mg/m:!), methy11 ethyl ketone (800 ppm, 2,345 mg/m3) and methylchlorofolm (800 ppm, 4,345 mg/m 3 ) :£or fuur weeks. Increased liver weights and liver to body weight ratios were observed~or all the ,solvents except n-hexane. An ,increased in Vlitro formati'on of certain metabolites of all the investigated substrates was found only illl the raits exposed to xylene. The in vitro microsomal metabolism of biphenyl, benzo(a)'PY'rene, 4-androstene-3,17-d~one and 5a-androstane3a, 17ji-diol in combination wHh sodium dodecyl sullfate-polyacrylamide gel electrophoresis showed that n-hexane was wi1!hout effect on rat liver microsomal cytochrome P-450 and that methyl ethyl ketone and mebhylc'hloroform depressed the formation of two metabolites of androstenedione but did not alter the concentration of cytochrome P-450 under the experimental e,onditions used. Xylene was shown to be a phenobarbital-like inducer of rat liver microsomal cytochrome P-450.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks.

Toftgárd¹,

Nilsen²,

Gustafsson

1981

Scand J Work Environ Health

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“…Epidemiological studies indicate that populations exposed to carcinogenic PAHs increase in levels of several markers of genotoxicity, including PAH DNA adducts, chromosome aberrations (CA), sister chromatid exchanges (SCE), and ras oncogene overexpression (3,4). Previous studies have shown that B[a]PDE and 5-MCDE can cause mutation by forming DNA adducts, and initiate tumor formation (7,8). There is also some evidence that PAHs and their metabolites affect cellular signaling pathways (15)(16)(17)44 (45).…”

Section: Ap-1 Transactivation Was Required For Vegf Induction By B[a]mentioning

confidence: 99%

Effects of Polycyclic Aromatic Hydrocarbons (PAHs) on Vascular Endothelial Growth Factor Induction through Phosphatidylinositol 3-Kinase/AP-1-dependent, HIF-1α-independent Pathway

Ding

Chen

et al. 2006

Journal of Biological Chemistry

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Previous studies have demonstrated that exposure to polycyclic aromatic hydrocarbons (PAHs) and its derivatives is associated with an increased risk of skin cancers, and the carcinogenic effect of PAHs is thought to involve both tumor initiation and promotion. Whereas PAH tumor initiation is well characterized, the mechanisms involved in the tumor promotion of PAHs remain elusive. In the present study, we investigated the effects of PAHs on vascular endothelial growth factor 6 -8). 5-MCDE has also been found to be a strong complete carcinogen (9 -11). Therefore, PHAs are important compounds in the etiology of human cancers. Carcinogenesis is a multistage process that consists of initiation, promotion, and progression (13). Initiation is a rapid and irreversible course, whereas promotion is a long term process requiring chronic exposure to a certain compound with tumor promotion activities (14). It is very likely that PAHs contribute to carcinogenesis through involvement at these multiple stages (15, 16). The mutagenic effects of PAHs, which are responsible for tumor initiation, have been extensively documented (5, 9 -12). However, their tumor promotion effects, which are mainly mediated by activation of transcription factors, are not well understood. It is thought that the rate-limiting steps in multistage carcinogenesis occur during tumor promotion and tumor progression. Thus, the identification of signaling pathways involved in PAH tumor promotion is not only essential for understanding the tumorigenesis of PAH compounds, but also in providing useful information for tumor chemoprevention. So it is practically important to compare among the parental PAHs, their derivatives as well as their analogs, the potential effects on various signaling pathways and downstream target genes. Because vascular endothelial growth factor (VEGF) is one of the key growth factors involved in carcinogenesis, we here investigate the effects of subgroups of PAHs, including B[a]P and its derivative B[a]PDE, 5-MCDE, and its analog CDE, on VEGF induction, as well as the signaling pathways leading to this induction. * This work was supported in part by Grants CA112557, CA103180, and CA094964 from the NCI, National Institutes of Health and Grants ES012451, ES000260, and ES010344 from the NIEHS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. -7,8-diol-9,10-epoxide; CDE, chrysene-1,2-diol-3,4-epoxide; 5-MCDE, (Ϯ)-anti-5-methylchrysene-1,2-diol-3,4-epoxide; FBS, fetal bovine serum; MEM, Eagle's minimal essential medium; PI-3K, phosphatidylinositol 3-kinase; EMSA, electrophoretic mobility shift assay; PBS, phosphate-buffered saline; RT, reverse transcriptase.

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“…It is known that bay region diol epoxides are mutagenic (57)(58)(59)(60)(61)(62)(63)(64), have transforming activity in mammalian cells (27,61), are carcinogenic in newborn mice (60,(65)(66)(67), and are initiators in the cells of mouse skin (42,(58)(59)(60)(65)(66)(67)(68). The mutagenicity and carcinogenicity, added to the fact that these adducts are formed in vivo leads to the hypothesis that these adducts play a role in the initiation of PAH-induced cancer.…”

Section: Introductionmentioning

confidence: 99%

Formation and Persistence of Benzo(a)pyrene Metabolite-DNA Adducts

Stowers¹,

Anderson²

1985

Environmental Health Perspectives

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Benzo(a)pyrene (BP) and other polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants and are suspected to be carcinogenic in man. The in vivo formation of BP metabolite-DNA adducts has been characterized in a variety of target and nontarget tissues of mice and rabbits. Tissues included were lung, liver, forestomach, colon, kidney, muscle, and brain. The major adduct identified in each tissue was the (+ )-7,B,8a-dihydroxy-9a,lOa-epoxy-7,8,9,10-tetrahydro-BP (BPDEI)-deoxyguanosine adduct. A 713,8a-dihydroxy-93,1013-epoxy-7,8,9,10-tetrahydro-BP (BPDEII)-deoxyguanosine adduct, a ( -)-BPDEI-deoxyguanosine adduct, and an unidentified adduct were also observed. The adduct levels are unexpectedly similar in all the tissues examined from the same BP-treated animal. For example, the BPDEI-DNA adduct levels in muscle and brain of mice were approximately 50%o of those in lung and liver at each oral BP dose used. We have also examined adduct levels formed in vivo in several cell types of lung and liver. Macrophages, type II cells, and Clara cells from lung and hepatocytes and nonpparenchymal cells from liver were isolated from BP-treated rabbits. BPDEI-deoxyguanosine adduct was observed in each cell type and, moreover, the levels were similar in various cell types. These and previous results strongly suggest that DNA in many human tissues is continuously damaged from known exposure of humans to BP and other PAH. Moreover, DNA adducts formed from BP are persistent in lung and brain. The persistence of adducts in cell types that have slow turnover rates could result in significant accumulation of adducts from long-term exposure to low levels of BP. BPDEI-DNA adducts and other bulky adducts are known to inhibit replication and transcription in in vitro systems. Even if environmental exposure to PAH is too low to induce neoplasia, the accumulation of DNA adducts may produce aberrations in transcripts of genetic information in various cells and lead to other toxic effects. Thus, further elucidation of the mechanism by which BP(PAH) metabolites bind to DNA of specific cell types and of the cellselective repair of the adducts should enhance our understanding of the potential health risk from exposure to this class of environmental pollutants.

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Mutagenicity and Carcinogenicity of Benzo[a]pyrene and Benzo[a]pyrene Derivatives

Cited by 50 publications

References 29 publications

Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks.

Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks.

Effects of Polycyclic Aromatic Hydrocarbons (PAHs) on Vascular Endothelial Growth Factor Induction through Phosphatidylinositol 3-Kinase/AP-1-dependent, HIF-1α-independent Pathway

Formation and Persistence of Benzo(a)pyrene Metabolite-DNA Adducts

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