Genetic variations of CYP2B6 gene were associated with plasma BPDE-Alb adducts and DNA damage levels in coke oven workers |
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Authors: | Huang Guoxiang Guo Huan Wu Tangchun |
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Affiliation: | a Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 440-746, Republic of Korea b Division of Toxicology, Pharmacokinetics, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 440-746, Republic of Korea c National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration, Seoul, Republic of Korea d College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan 609-735, Republic of Korea e College of Pharmacy, Inje University, Gimhae, Republic of Korea |
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Abstract: | This study was designed to investigate the molecular mechanism underlying the chemopreventive effects of methionine on benzo[a]pyrene (B[a]P)-DNA adducts formation in HepG2 cells. Methionine significantly inhibited B[a]P-DNA adduct formation in HepG2 cells. Methionine significantly decreased the cellular uptake of [3H] B[a]P, but increased the cellular discharge of [3H] B[a]P from HepG2 cells into the media. B[a]P significantly lowered total cellular glutathione (GSH) level, but co-cultured with B[a]P and methionine, gradually attenuated intracellular GSH levels in a concentration-dependent manner, which was markedly higher at 20-500 μM methionine. The cellular proteins of treated cells were resolved by 2D-polyacrylamide gel electrophoresis. Proteomic profiles showed that phase II enzymes such as glutathione S-transferase (GST) omega-1, GSTM3, glyoxalase I (GLO1) and superoxide dismutase (SOD) were down-regulated by B[a]P treatment, whereas cathepsin B (CTSB), Rho GDP-dissociation inhibitor alpha (Rho-GDP-DIA), histamine N-methyltransferase (HNMT), spermidine synthase (SRM) and arginase-1 (ARG1) were up-regulated by B[a]P. B[a]P and methionine treatments, GST omega-1, GSTM3, GLO1 and SOD were significantly enhanced compared to B[a]P alone. Similarly, methionine was effective in diminishing the B[a]P-induced up-regulation of CTSB, Rho-GDP-DIA, HNMT, SRM and ARG1. Our data suggests that methionine might exert a chemoprotective effect on B[a]P-DNA adduct formation by attenuating intracellular GSH levels, blocking the uptake of B[a]P into cells, or by altering expression of proteins involved in DNA adduct formation. |
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Keywords: | ARG1, arginase-1 B[a]P, benzo[a]pyrene BPDE, benzo[a]pyrene-diolepoxide CERCLA, The Comprehensive Environmental Response, Compensation, and Liability Act CTSB, cathepsin B HNMT, histamine N-methyltransferase IARC, International Agency for Research on Cancer GST, glutathione S-transferase GLO1, glyoxalase I PMF, peptide mass fingerprinting Rho-GDP-DIA, Rho GDP-dissociation inhibitor alpha SAM, S-adenosylmethionine SOD, superoxide dismutase SRM, spermidine synthase TFA, trifluoroacetic acid |
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