Carcinogenesis, Vol 19, 433-436, Copyright © 1998 by Oxford University Press
K Sundberg, AS Johansson, G Stenberg, M Widersten, A Seidel, B Mannervik and B Jernstrom
Previous studies have identified allelic variants of the human glutathione
transferase (GST) Pi gene and showed that the two different encoded
proteins with isoleucine (GSTP1-1/I-105) or valine (GSTP1-1/V- 105) at
position 105, respectively, differ significantly in their catalytic
activities with model substrates. Moreover, recent epidemiological studies
have demonstrated that individuals differing in the expression of these
allelic variants also differ in susceptibility to tumour formation in
certain organs, including such in which polycyclic aromatic hydrocarbons
(PAH) may be etiological factors. In the present study the catalytic
efficiencies (kcat/Km) of these GSTP1-1 variants were determined with a
number of stereoisomeric bay-region diol epoxides, known as the ultimate
mutagenic and carcinogenic metabolites of PAH, including those from
chrysene, benzo[a]pyrene and dibenz[a,h]anthracene. In addition, GSTP1-1
mutants in which amino residue 105 is alanine (GSTP1-1/A-105) or tryptophan
(GSTP1-1/W-105) have been constructed and characterized. GSTP1-1/V-105 was
found to be more active than GSTP1-1/I-105 in conjugation reactions with
the bulky diol epoxides of PAH, being up to 3-fold as active towards the
anti- and syn-diol epoxide enantiomers with R-absolute configuration at the
benzylic oxiranyl carbon. Comparing the four enzyme variants, GSTP1-1/A-
105 generally demonstrated the highest kcat/Km value and GSTP1-1/W-105 the
lowest with the anti-diol epoxides. A close correlation was observed
between the volume occupied by the amino acid residue at position 105 and
the value of kcat/Km. With the syn-diol epoxides, such a correlation was
observed with alanine, valine and isoleucine, whereas tryptophan was
associated with increased kcat/Km values. The mutational replacement of
isoleucine with alanine or tryptophan at position 105 did not alter the
enantio selectivity of the GSTP1-1 variants compared with the naturally
occurring allelic variants GSTP1-1/I-105 and GSTP1- 1/V-105. Since the
amino acid at position 105 forms part of the substrate binding site
(H-site) the effect of increasing bulkiness is expected to cause restricted
access of the diol epoxide and proper alignment of the two reactants for
efficient glutathionylation. In conclusion, the present study indicates
that individuals who are homozygous for the allele GSTP1* B (coding for
GSTP1-1/V-105) display a higher susceptibility to malignancy because of
other factors than a decreased catalytic efficiency of GSTP1-1/V-105 in the
detoxication of carcinogenic diol epoxides of benzo[a]pyrene or
structurally related PAH.
ARTICLES
Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1-1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons
Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, Stockholm, Sweden.
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