Journal article
Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis
Pharmacogenetics and genomics, Vol.21(2), pp.55-65
02/2011
Handle:
https://hdl.handle.net/2376/114312
PMCID: PMC3019304
PMID: 21164388
Abstract
UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of various endogenous and xenobiotic compounds, including carcinogens and chemotherapeutic agents. The goal of the present study was to examine UGT2A1 expression in human tissues, determine its glucuronidation activity against tobacco carcinogens, and assess the potential functional role of UGT2A1 missense single nucleotide polymorphisms on UGT2A1 enzyme activity. As determined by reverse-transcription polymerase chain reaction, UGT2A1 was expressed in aerodigestive tract tissues including trachea, larynx and tonsil, and was also expressed in lung and colon; no expression was observed in breast, whole brain, pancreas, prostate, kidney, liver or esophagus. Real-time PCR suggested that UGT2A1 exhibited highest expression in the lung, followed by trachea > tonsil > larynx > colon > olfactory tissue. Cell homogenates prepared from wild-type UGT2A1
75Lys308Gly
-over-expressing HEK293 cells showed significant glucuronidation activity, as observed by reverse-phase UPLC, against a variety of polycyclic aromatic hydrocarbons (PAHs) including, 1-hydroxy-benzo(a)pyrene, benzo(a)pyrene-7,8-diol, and 5-methylchrysene-1,2-diol. No activity was observed in UGT2A1-over-expressing cell homogenate against substrates that form
N
-glucuronides, such as NNAL, nicotine, or
N
-OH-PhIP. A significant (p<0.05) ~25% decrease in glucuronidation activity (V
max
/K
M
) was observed against all PAH substrates for the UGT2A1
75Arg308Gly
variant as compared to homogenates from wild-type UGT2A1
75Lys308Gly
; no activity was observed for cell homogenates over-expressing the UGT2A1
75Lys308Arg
variant for all substrates tested. These data suggest that UGT2A1 is an important detoxification enzyme in the metabolism of PAHs within target tissues for tobacco carcinogens, and functional polymorphisms in UGT2A1 may play a role in tobacco-related cancer risk.
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Details
- Title
- Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis
- Creators
- Ryan T Bushey - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033, USAGang Chen - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033, USAAndrea S Blevins-Primeau - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033, USAJacek Krzeminski - Chemical Carcinogenesis and Chemoprevention Program, Penn State Cancer Institute, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033, USAShantu Amin - Chemical Carcinogenesis and Chemoprevention Program, Penn State Cancer Institute, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033, USAPhilip Lazarus - Molecular Epidemiology and Cancer Control Program, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
- Publication Details
- Pharmacogenetics and genomics, Vol.21(2), pp.55-65
- Academic Unit
- Pharmaceutical Sciences, Department of
- Identifiers
- 99900547720901842
- Language
- English
- Resource Type
- Journal article