Chemical Carcinogenesis. Part 151. Synthesis of Fjord Region Diol Epoxides as Potential Ultimate Carcinogens of Dibenzo[a,l]pyrene

Krzeminski, Jacek; Lin, Jingqiang; Amin, Shantu; Hecht, Stephen S.

doi:10.1021/tx00038a002

Cited by 47 publications

(39 citation statements)

References 7 publications

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“…DBC, DBC-11,12-diol, DBC-11,12,13,14-teraols, B[a]P-7,8-diol, and B[a]P-7,8,9,10-tetraols were synthesized according to previously reported methods (Krzeminski et al, 1994; Luch et al, 1998; Sharma et al, 2004). B[a]P, sodium sulfate, sulfuric acid, acetone, methanol, ethyl acetate, phosphate buffered saline, magnesium chloride, tris acetate, potassium chloride, potassium pyrophosphate, ethylenediaminetetracetic acid (EDTA) and nicotinamide adenine dinucleotide phosphate (NADPH) were purchased from Sigma (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes

Crowell¹,

Hanson-Drury²,

Williams³

et al. 2014

Toxicology Letters

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Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and often carcinogenic contaminants released into the environment during natural and anthropogenic combustion processes. Benzo[a]pyrene (B[a]P) is the prototypical carcinogenic PAH, and dibenzo[def,p]chrysene (DBC) is a less prevalent, but highly potent transplacental carcinogenic PAH. Both are metabolically activated by isoforms of the cytochrome P450 enzyme superfamily to form reactive carcinogenic and cytotoxic metabolites. Metabolism of B[a]P and DBC was studied in hepatic microsomes of male Sprague-Dawley rats, naïve and pregnant female B6129SF1/J mice, and female humans, corresponding to available pharmacokinetic data. Michaelis–Menten saturation kinetic parameters including maximum rates of metabolism (VMAX, nmol/min/mg microsomal protein), affinity constants (KM, μM), and rates of intrinsic clearance (CLINT, ml/min/kg body weight) were calculated from substrate depletion data. CLINT was also estimated from substrate depletion data using the alternative in vitro half-life method. VMAX and CLINT were higher for B[a]P than DBC, regardless of species. Clearance for both B[a]P and DBC was highest in naïve female mice and lowest in female humans. Clearance rates of B[a]P and DBC in male rat were more similar to female human than to female mice. Clearance of DBC in liver microsomes from pregnant mice was reduced compared to naïve mice, consistent with reduced active P450 protein levels and elevated tissue concentrations and residence times for DBC observed in previous in vivo pharmacokinetic studies. These findings suggest that rats are a more appropriate model organism for human PAH metabolism, and that pregnancy's effects on metabolism should be further explored.

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Section: Methodsmentioning

confidence: 99%

In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes

Crowell¹,

Hanson-Drury²,

Williams³

et al. 2014

Toxicology Letters

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“…DB[ a,l ]P- trans -11,12-diol was synthesized following our previously reported methods 28,29 . Caution: Diol epoxides from polycyclic aromatic hydrocarbons are carcinogens, and thus experimental handling must be carried out under special safety conditions according to the National Cancer Institute guidelines .…”

Section: Methodsmentioning

confidence: 99%

Characterization of Dibenzo[a,l]pyrene-trans-11,12-diol (Dibenzo[def,p]chrysene) Glucuronidation by UDP-Glucuronosyltransferases

Olson

Sun

Chen

et al. 2011

Chem. Res. Toxicol.

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Dibenzo[a,l]pyrene (DB[a,l]P) (dibenzo[def,p]chrysene) is a highly carcinogenic polycyclic aromatic hydrocarbon (PAH) that has been identified in tobacco smoke and is found in our environment due to incomplete combustion of organic matter. Its metabolites are known to form stable DNA adducts in bacteria and mammalian cells, and can lead to tumors in animal models. Glucuronidation of major metabolites of DB[a,l]P by the uridine-5’-diphosphate glucuronosyltransferase (UGT) family of enzymes is an important route of detoxification of this pro-carcinogen. The focus of the current study was to characterize the glucuronidation of the pro-carcinogenic enantiomers DB[a,l]P-(+)-trans-11S,12S–diol and DB[a,l]P-(−)-trans-11R,12R–diol. Glucuronidation assays with HEK293 cell lines over-expressing individual human UGT enzymes demonstrated that UGTs 1A1, 1A4, 1A7, 1A8, 1A9, 1A10, and 2B7 glucuronidated one or both DB[a,l]P-trans-11,12-diol enantiomers. Three glucuronide conjugates were observed in activity assays with UGTs 1A1 and 1A10, while two glucuronides were formed by UGTs 1A7, 1A8, and 1A9, and one glucuronide was made by UGT1A4 and UGT2B7. Enzyme kinetic analysis indicated that UGT1A9 was the most efficient UGT at forming both the (+)-DB[a,l]P-11-Gluc and (−)-DB[a,l]P-11-Gluc products while UGTs 1A1 and 1A10 were the most efficient at forming the (+)-DB[a,l]P-12-Gluc product (as determined by the kcat/KM). Incubations with human liver microsomes showed formation of three diastereomeric glucuronide products: (+)-DB[a,l]P-11-Gluc, (+)-DB[a,l]P-12-Gluc, and (−)-DB[a,l]P-11-Gluc, with an average overall ratio of 31 : 32 : 37 in four liver specimens. Human bronchus and trachea tissue homogenates demonstrated glucuronidation activity against both DB[a,l]P-trans-11,12-diol enantiomers, with both tissues producing the (+)-DB[a,l]P-11-Gluc and (+)-DB[a,l]P-12-Gluc with little or no formation of (−)-DB[a,l]P-11-Gluc. These results indicate that multiple UGTs are involved in the stereospecific glucuronidation of DB[a,l]P-trans-11,12-diol in a pattern consistent with their expression in respiratory tract tissues, and that glucuronidation may be an important first-line detoxification mechanism of DB[a,l]P metabolites.

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“…After centrifugation, the pellet (exclusive of cartilage and bones) was resuspended and fibroblasts were cultured in DMEM containing 10% fetal bovine serum. (ϩ)-Syn-and (Ϫ)-anti-DB[a,l]PDE were synthesized as described (29,37,38).…”

Section: Methodsmentioning

confidence: 99%

DNA Damage, Repair, and Mutation Induction by (+)- Syn and (−)- Anti -Dibenzo[ a,l ]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells

et al. 2004

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Chemical Carcinogenesis. Part 151. Synthesis of Fjord Region Diol Epoxides as Potential Ultimate Carcinogens of Dibenzo[a,l]pyrene

Cited by 47 publications

References 7 publications

In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes

In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes

Characterization of Dibenzo[a,l]pyrene-trans-11,12-diol (Dibenzo[def,p]chrysene) Glucuronidation by UDP-Glucuronosyltransferases

DNA Damage, Repair, and Mutation Induction by (+)- Syn and (−)- Anti -Dibenzo[ a,l ]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells

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