Expression of hGSTP1 alleles in human lung and catalytic activity of the native protein variants towards 1-chloro-2,4-dinitrobenzene, 4-vinylpyridine and (+)-anti benzo[a]pyrene-7,8-diol-9,10-oxide.
The human glutathione S-transferase (GST) P1 alleles coding for Val(105) (hGSTP1*B and/or P1*C) are over- represented in lung cancer patients. However, the corresponding recombinant Val(105) protein variants tend to show higher catalytic activity than the Ile(105) variants towards bay-region diol epoxides that are thought to be etiological agents in lung cancer. We have examined 29 normal human lung samples with respect to several factors that could confound relationships between hGSTP1 allele type and cancer susceptibility, namely, inter-individual and allele-specific variation of hGSTP1 expression, and differences between the catalytic properties of the native and recombinant hGSTP1-1 variant protein products. hGSTP1 expression varied 7-fold among individuals but was independent of hGSTP1*A, P1*B or P1*C allele type. hGST subunits A1, A2, M1 and M3 were minor components, similarly variable in expression. Despite this variability of expression, the levels of hGSTP1 expression linearly correlated with those of the next most highly expressed GST, hGSTM3, even though the genes for these GSTs are on different chromosomes. Differences between the native protein variants, using 1-chloro-2,4-dinitrobenzene and (+)-anti-benzo[a]pyrene diolepoxide as substrates, were more marked than those between the recombinant variants. However, the order of differential catalytic specificity was the same for native and recombinant variants. Neither the expression of the hGSTP1 alleles nor the catalytic properties of the protein variants appears to provide a simple mechanistic rationale for the observed over-representation of the hGSTP1*B and/or 1*C alleles in lung cancer.
Coles
B
B
Division of Molecular Epidemiology, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA. bcoles@nctr.fda.gov
Yang
M
M
Lang
N P
NP
Kadlubar
F F
FF
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000493:pharmacokinetics; D000483:Alleles; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D002384:Catalysis; D004137:Dinitrochlorobenzene / Q000378:metabolism / Q000493:pharmacokinetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007206:Individuality; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D002273:Carcinogens; D004137:Dinitrochlorobenzene; D007527:Isoenzymes; D011725:Pyridines; D011994:Recombinant Proteins; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C029351:4-vinylpyridine