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

Kristine C Olson; Dongxiao Sun; Gang Chen; Arun K Sharma; Shantu Amin; Ira J Ropson; Thomas E Spratt; Philip Lazarus

doi:10.1021/tx200178v

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

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

Kristine C Olson, Dongxiao Sun, Gang Chen, Arun K Sharma, Shantu Amin, Ira J Ropson, Thomas E Spratt and Philip Lazarus

Chemical research in toxicology, Vol.24(9), pp.1549-1559

09/19/2011

DOI: https://doi.org/10.1021/tx200178v

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https://hdl.handle.net/2376/112119

PMCID: PMC3177992

PMID: 21780761

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Abstract

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 -11 S ,12 S –diol and DB[ a,l ]P-(−)- trans -11 R ,12 R –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 k cat / K M ). 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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Title: Characterization of Dibenzo[a,l ]pyrene-trans-11,12-diol (Dibenzo[def,p]chrysene) Glucuronidation by UDP-glucuronosyltransferases
Creators: Kristine C Olson - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, Hershey, PA 17033
Dongxiao Sun - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, Hershey, PA 17033
Gang Chen - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, Hershey, PA 17033
Arun K Sharma - Chemical Carcinogenesis and Chemoprevention Program, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
Shantu Amin - Chemical Carcinogenesis and Chemoprevention Program, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
Ira J Ropson - Department of Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, PA 17033
Thomas E Spratt - Chemical Carcinogenesis and Chemoprevention Program, Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
Philip Lazarus - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, Hershey, PA 17033
Publication Details: Chemical research in toxicology, Vol.24(9), pp.1549-1559
Academic Unit: Pharmaceutical Sciences, Department of
Grant note: R01 DE013158-09 || DE / National Institute of Dental and Craniofacial Research : NIDCR R01 DE013158-08 || DE / National Institute of Dental and Craniofacial Research : NIDCR R01 DE013158-11 || DE / National Institute of Dental and Craniofacial Research : NIDCR R01 DE013158-10 || DE / National Institute of Dental and Craniofacial Research : NIDCR
Identifiers: 99900547588001842
Language: English
Resource Type: Journal article