NAD(P)H Quinone Dehydrogenase 1, or NQO1, is an enzyme found throughout the human body. It is a flavin-containing enzyme located in the cytosol that forms homodimers. NQO1 performs a two-electron reduction, utilizing either NADH or NADPH as electron donors. This activity helps protect cells from environmental and internal stressors.
Understanding NQO1: The Body’s Detoxifier
NQO1 functions as a detoxification enzyme by catalyzing the two-electron reduction of quinones to hydroquinones. Quinones are reactive compounds that can generate harmful reactive oxygen species (ROS) through redox cycling. By converting quinones into their more stable hydroquinone forms, NQO1 prevents the formation of damaging semiquinone free radicals and subsequent oxidative stress.
NQO1 is present in epithelial and endothelial tissues, which are often exposed to compounds entering the body, highlighting its role in protecting these cells. It also participates in the metabolism of endogenous quinones, such as ubiquinone and vitamin E quinone, reducing them to their antioxidant hydroquinone forms. This action helps protect cellular membranes from damage caused by lipid peroxidation.
NQO1’s Role in Cancer
NQO1 plays a complex, dual role in cancer, sometimes acting protectively and other times contributing to disease progression or drug resistance. It can function as a tumor suppressor by stabilizing the p53 protein, which regulates cell growth and death. When NQO1 levels are elevated under cellular stress, it inhibits p53 degradation, promoting its accumulation and protective effects against tumorigenesis.
Conversely, NQO1 can also contribute to drug resistance in certain cancers. Some chemotherapy drugs, like mitomycin C, are activated by NQO1, leading to DNA damage in cancer cells. However, high NQO1 levels in tumors can also lead to resistance to other chemotherapeutic agents by detoxifying compounds or altering pathways that influence drug efficacy. Elevated NQO1 expression has been linked to tumor progression, aggressiveness, and poorer patient prognosis in various cancer types, including glioma, uveal melanoma, head and neck squamous cell carcinoma, and kidney renal papillary cell carcinoma. This makes NQO1 a potential target for personalized anticancer therapies, as researchers explore strategies to either induce its activity for specific drug activation or inhibit it to overcome resistance.
NQO1 and Other Health Conditions
Beyond its involvement in cancer, NQO1 also plays a role in other health conditions, particularly neurodegenerative diseases, due to its antioxidant properties. In Parkinson’s disease, NQO1 expression increases in early and intermediate stages, suggesting a protective response against oxidative stress from dopamine metabolism. However, NQO1 levels may decrease in later stages as dopaminergic neurons are lost.
NQO1 is also associated with Alzheimer’s disease pathology, where altered expression of the enzyme is observed. Mitochondrial dysfunction and oxidative stress are factors in Alzheimer’s progression, and NQO1’s ability to activate antioxidant enzymes offers neuroprotection. Additionally, NQO1 has been implicated in cardiovascular health, with animal studies suggesting a protective role against conditions like atherogenesis, dyslipidemia, and insulin resistance. Genetic variations in the NQO1 gene have been linked to an increased risk of adverse lipid profiles and coronary artery disease.
Factors Affecting NQO1 Activity
NQO1 enzyme activity can be influenced by genetic and dietary factors. Genetic variations in the NQO1 gene can lead to altered enzyme function. For example, the NQO12 allele (rs1800566 or 609C/T) results in a proline-to-serine change at amino acid position 187, often leading to reduced or lost NQO1 enzyme activity. Over 25% of the global population carries this variant, with frequencies varying among ethnic groups.
Dietary compounds can also induce NQO1 expression. Sulforaphane, found in cruciferous vegetables like broccoli, activates Nrf2, a master regulator of antioxidant responses, which upregulates NQO1 mRNA expression. Curcumin from turmeric, and resveratrol found in grapes and berries, also induce NQO1 expression, often through Nrf2 pathway activation. These compounds, along with others like piperine, may contribute to cellular defense by boosting NQO1 activity.