Catalytic efficiencies of allelic variants of human glutathione S-transferase Pi in the glutathione conjugation of alpha, beta-unsaturated aldehydes.
The catalytic efficiencies of the allelic variants of human glutathione (GSH) S-transferase Pi (hGSTP1-1), which differ in their primary structures by the amino acids in positions 104 (isoleucine or valine) and/or 113 (alanine or valine), in the GSH conjugation (detoxification) of acrolein and crotonaldehyde have been determined. The k(cat)/K(m) values for hGSTP1-1 isoforms I104,A113 (IA), I104, V113 (IV), V104,A113 (VA) and V104,V113 (VV) toward acrolein were 129+/-3, 116+/-3, 128+/-4 and 92+/-3 mM(-1) s(-1), respectively. The catalytic efficiencies of the hGSTP1-1 variants IA, IV, and VA in the GSH conjugation of acrolein were statistically significantly higher (at P=0.05) compared with the VV isoform. On the other hand, the catalytic efficiencies of the hGSTP1-1 isoforms IA, IV, VA and VV toward crotonaldehyde (16+/-2, 12+/-1, 17+/-2, and 12+/-2 mM(-1)s(-1), respectively) were not statistically significantly different from each other. Our results suggest that hGSTP1-1 polymorphism may be an important factor in differential susceptibility of individuals to the toxic effects of acrolein, which is a widely spread environmental pollutant and generated endogenously during metabolic activation of anticancer drug cyclophosphamide.
Pal
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Cancer Research Laboratory, Mercy Hospital of Pittsburgh, PA 15219, USA.
Hu
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Zimniak
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Singh
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D000171:Acrolein / Q000378:metabolism / Q000633:toxicity; D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000483:Alleles; D002384:Catalysis; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D011110:Polymorphism, Genetic; D020033:Protein Isoforms
D000447:Aldehydes; D007527:Isoenzymes; D020033:Protein Isoforms; D000171:Acrolein; C012796:2-butenal; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D005978:Glutathione