Nrf2 gene as a double-edged sword: Clinical relevance of its genetic polymorphisms

Abstract

In all aerobic organisms on Earth, molecular oxygen is essential for cellular respiration, and our body consisting of those cells is continuously exposed to " oxidative stress " . In response to oxidative stress, NF-E2-related transcription factor (Nrf2) encoded by the Nrf2 gene is considered to play a pivotal role in cellular defense via transcriptional up-regulation of many downstream genes, including those for metabolizing enzymes and transporters essential for cellular function. However, it is also true that the Nrf2 gene is regarded as a double-edged sword. While it plays a role in protecting normal cells from external toxic challenges and oxidative stress, the Nrf2 gene can also endow cancer cells resistance to anticancer drugs. The Nrf2 protein interacts with the antioxidant responsive element (ARE) located in the promoter region of the Nrf2 gene as well as its downstream target genes. Genetic polymorphisms and/or mutations in the Nrf2 gene have hitherto been identified in human samples, one single nucleotide polymorphism (SNP; -617C>A; rs6721961) in the ARE-like loci of the human Nrf2 gene reportedly affects the positive feedback loop of transcriptional activation of the Nrf2 gene. Ethnic group-dependent difference is observed for that SNP, where the frequency of the -617A allele is high in Japanese, Taiwanese, and Chinese populations. These allele frequency differences in the Nrf2 gene may reflect genetic alterations and selection that took place during inter-continental migrations of Homo sapiens.