Activity of allelic variants of Pi class human glutathione S-transferase toward chlorambucil.
Clinical efficacy of alkylating anticancer drugs, such as chlorambucil, is often limited by the emergence of drug resistant tumor cells. Increased glutathione (GSH) conjugation (inactivation) of alkylating anticancer drugs or their activated metabolites due to overexpression of the Pi class GSH S-transferase (hGSTP1-1) is believed to be an important mechanism in tumor cell resistance to alkylating agents. Interestingly, the hGSTP1 locus is polymorphic in human populations and involves amino acid residues in positions 104 (isoleucine or valine) and/or 113 (alanine or valine). Here, we report that the allelic variants of hGSTP1-1 significantly differ in their efficiency in catalyzing the GSH conjugation of chlorambucil. Catalytic efficiency of the hGSTP1-1(I104,A113) isoform toward chlorambucil was approximately 2.5-, 7.5- and 15-fold higher compared with I104,V113, V104,A113 and V104,V113 variants of hGSTP1-1, respectively. The results of the present study suggest that hGSTP1-1 polymorphism may be an important factor in GST-mediated tumor cell resistance to some alkylating agents.
Pandya
U
U
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Srivastava
S K
SK
Singhal
S S
SS
Pal
A
A
Awasthi
S
S
Zimniak
P
P
Awasthi
Y C
YC
Singh
S V
SV
D000409:Alanine / Q000737:chemistry; D000477:Alkylating Agents / Q000494:pharmacology; D000483:Alleles; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002384:Catalysis; D002699:Chlorambucil / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007532:Isoleucine / Q000737:chemistry; D007700:Kinetics; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D013852:Thiotepa / Q000494:pharmacology; D014633:Valine / Q000737:chemistry
D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D020033:Protein Isoforms; D007532:Isoleucine; D002699:Chlorambucil; D013852:Thiotepa; D005982:Glutathione Transferase; D014633:Valine; D000409:Alanine