Pandya U, Srivastava S K, Singhal S S, Pal A, Awasthi S, Zimniak P, Awasthi Y C, Singh S V
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Biochem Biophys Res Commun. 2000 Nov 11;278(1):258-62. doi: 10.1006/bbrc.2000.3787.
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.
烷化剂抗癌药物（如苯丁酸氮芥）的临床疗效常常受到耐药肿瘤细胞出现的限制。由于Pi类谷胱甘肽S-转移酶（hGSTP1-1）的过表达，烷化剂抗癌药物或其活化代谢产物的谷胱甘肽（GSH）结合（失活）增加，被认为是肿瘤细胞对烷化剂耐药的重要机制。有趣的是，hGSTP1基因座在人群中具有多态性，涉及104位（异亮氨酸或缬氨酸）和/或113位（丙氨酸或缬氨酸）的氨基酸残基。在此，我们报告hGSTP1-1的等位基因变体在催化苯丁酸氮芥的GSH结合效率上存在显著差异。与hGSTP1-1的I104、V113、V104、A113和V104、V113变体相比，hGSTP1-1（I104，A113）同工型对苯丁酸氮芥的催化效率分别高出约2.5倍、7.5倍和15倍。本研究结果表明，hGSTP1-1多态性可能是GST介导的肿瘤细胞对某些烷化剂耐药的重要因素。
