Predictive role of polymorphic variants of phase II drug metabolising enzyme in modulating toxicity in North Indian lung cancer patients undergoing chemotherapy

Abstract

1. Genetic polymorphism of drug-metabolising enzymes such as NQO1, SULT1A1, EPHX1, and NAT2 alters its activity which hampers the detoxification and disposal of chemotherapeutic compounds. Thus, in the present study, we have comprehensively investigated the associations between SNPs of the Phase II detoxifying genes and its relationship towards platinum-induced toxicity of lung cancer patients.

2. NQO1 (609 C > T), SULT1A1 (Arg²¹³ His), EPHX1 (Tyr¹¹³His, His¹³⁹Arg), and NAT2 (481 C > T, 803 A > G, 590 G > A, 857 G > A) were evaluated in our study for their associated adverse events caused due to the administration of platinum-based chemotherapy to the lung cancer patients.

3. For NQO1 609 C > T polymorphism, the TT genotype showed reduced risk of constipation (OR = 0.10, p = 0.04) and anorexia (OR = 0.15, p = 0.03). For SULT1A1 Arg²¹³His, heterozygous genotype (Arg/His) (AOR = 0.38, p = 0.006) and combined genotype (Arg/His + His/His) were not associated with increased risk of nephrotoxicity (AOR = 0.38, p = 0.004). For NAT2, heterozygous (NAT2*4/*6) and combined genotypes (NAT2*4/*4+*4/*6) for NAT2*6 polymorphism exhibit 2.4 folds (p = 0.005), and two-folds (p = 0.01) increased risk of hematological toxicity. The heterozygous (AOR = 0.45, p = 0.004) and variant genotype (AOR = 0.39, p = 0.02) for NAT2*5C had decreased risk for hematological toxicity. The heterozygous genotype for NAT2*7 polymorphism showed two-fold increased risk for developing thrombocytopenia.

4. This study provides association of NAT2 polymorphic variants in predicting haematological toxicity.

Keywords:

• Phase II enzymes
• lung cancer
• polymorphism
• toxicity
• risk

Acknowledgement

The authors express gratitude to all the subjects who participated in this study. The authors thanks to Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India for providing samples and Thapar Institute of Engineering and Technology, Patiala, Punjab for providing the necessary infrastructure to carry out the research work.

Disclosure statement

There are no existing financial conflicts