Nrf2 Regulates the Expression of CYP2D6 by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).

AIMS: The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments. BACKGROUND: The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes. OBJECTIVES: The objectives of this study are to investigate the transcriptional regulation of CYP2D6 by Nrf2 and to analyze its role in PD and cancer. METHODS: Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of CYP2D6 was examined by RT-qPCR. The promoter activity of CYP2D6 and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and CYP2D6 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. RESULTS: In the present study, we demonstrated that Nrf2 down-regulated CYP2D6 mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of CYP2D6 promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on CYP2D6 expression, respectively. The expression levels of Nrf2 and CYP2D6 were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with CYP2D6. In liver cancer patients, decreased CYP2D6 levels were apparent and associated with a lower probability of survival. CONCLUSION: Our work revealed the inhibitory role of Nrf2 in regulating CYP2D6 expression. Moreover, Nrf2- dependent regulation of CYP2D6 can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.

Deletion Polymorphism of Angiotensin-Converting Enzyme Gene Is Associated with Low Muscle Mass in Elderly People in Jakarta, Indonesia.

Decline in muscle mass due to aging is a growing public health problem as it contributes to a decreased capacity for independent living among elderly people. A clear understanding of genetic factors is important, as it is known that angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism affects muscle mass, although the findings are frequently heterogeneous. This study was conducted to determine the association between ACE I/D polymorphism and muscle mass in elderly people. A total of 130 elderly people were recruited from nursing homes in Jakarta. Anthropometric components affecting the muscle mass were examined. Cross-sectional analyses were performed to compare data using t-test, ANOVA and ANCOVA, and linear regression. Genotyping of the ACE I/D polymorphisms was performed by PCR methods, and muscle mass was evaluated by BIA. Genotype distribution counts II 65.38%, ID 13.85%, and DD 20.77% were not consistent with the Hardy-Weinberg equilibrium (χ² = 22.2, df = 2; p < 0.01). Individuals with the DD genotype showed lower muscle mass that was significantly different compared to the muscle mass in individuals with the II/ID genotype (II 16.14 ± 0.38, ID 15.71 ± 0.59; DD 13.95 ± 0.61 kg), after adjusting for % fat as a covariate. The linear regression analysis showed that age, gender, weight, height, nutritional status, protein content, and waist, hip, and calf circumference were significant contributors to muscle mass. In the multivariate analysis, adjusted age and gender significantly correlated with muscle mass, with r² = 0.98, by the likelihood ratio test (p < 0.01). The genotype variability accounted for 2.65% of the DD genotype. This study showed that in an elderly population in Jakarta, the DD genotype was associated with low muscle mass. This result suggests the role of nutritional status as a potential mediator in the association between ACE gene and muscle mass.