rs1800566 — NQO1 Pro187Ser (C609T)

NQO1 Pro187Ser — The Quinone Detoxifier and CoQ10 Recycler

NQO1 (NAD(P)H:quinone oxidoreductase 1) is a Phase II detoxification enzyme¹¹ Phase II detoxification enzyme
Phase II enzymes conjugate or reduce reactive metabolites produced by Phase I enzymes, making them safer and easier to excrete that performs an unusual and critically important reaction: it reduces toxic quinones directly to stable hydroquinones via a two-electron transfer, completely bypassing the dangerous one-electron semiquinone radical²² semiquinone radical
A partially reduced quinone that reacts with oxygen to generate superoxide and other reactive oxygen species (ROS), causing oxidative damage to DNA, proteins, and lipids intermediate. This makes NQO1 a uniquely efficient detoxifier of quinone compounds, which arise from the metabolism of benzene, environmental pollutants, certain drugs, and normal cellular processes.

Beyond detoxification, NQO1 plays a second major role: it is one of the primary enzymes responsible for reducing CoQ10 (ubiquinone) to its active antioxidant form, ubiquinol. Researchers have proposed that NQO1 was selected during evolution primarily as a CoQ reductase³³ NQO1 was selected during evolution primarily as a CoQ reductase
Ross & Siegel 2017, Functions of NQO1 in Cellular Protection and CoQ10 Metabolism, and that its ability to detoxify xenobiotic quinones was a secondary gain of function. NQO1 also stabilizes the tumor suppressor proteins p53 and p73, protecting them from proteasomal degradation.

The rs1800566 variant (C609T in cDNA) causes a proline-to-serine substitution at position 187, falling in a region critical for the binding of the FAD cofactor⁴⁴ FAD cofactor
Flavin adenine dinucleotide, the essential cofactor that NQO1 requires to catalyze electron transfer reactions. This single amino acid change has dramatic consequences for protein stability and enzyme function.

The Mechanism

The Pro187Ser substitution disrupts the structural integrity of the NQO1 protein in a way that is unusually severe for a single missense variant. The serine at position 187 destabilizes the protein's tertiary structure, particularly at the FAD binding site in the N-terminal domain and the C-terminal domain important for substrate binding. The mutant protein is rapidly polyubiquitinated and degraded by the proteasome⁵⁵ rapidly polyubiquitinated and degraded by the proteasome
Siegel et al. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol, 2001, resulting in dramatically reduced intracellular NQO1 levels.

Heterozygotes (AG genotype, one variant copy) retain approximately one-third of normal enzyme activity. Homozygotes (AA genotype, two variant copies) retain only 2-4% of wild-type activity -- essentially no functional NQO1. This is because the mutant protein is so unstable that it is degraded almost as fast as it is made.

Without functional NQO1, quinone metabolism shifts to the one-electron pathway via cytochrome P450 reductase, generating reactive semiquinone radicals that produce superoxide, hydrogen peroxide, and hydroxyl radicals through redox cycling⁶⁶ redox cycling
A process where a molecule is repeatedly reduced and then re-oxidized by oxygen, generating a continuous stream of reactive oxygen species with each cycle. This increases oxidative stress and, in the context of benzene exposure, explains the heightened vulnerability to hematotoxicity.

The Evidence

Protein stability and activity: The foundational work by Siegel et al.⁷⁷ Siegel et al.
Siegel D et al. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol, 2001 demonstrated that while wild-type NQO1 persists in cells, the Pro187Ser mutant is rapidly ubiquitinated and sent to the proteasome for degradation. This elegant study explained why TT homozygotes have near-zero enzyme activity despite normal gene transcription.

Benzene toxicity: The NQO1-benzene connection was established in a landmark study of Chinese workers by Rothman et al.⁸⁸ Rothman et al.
Rothman N et al. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C>T mutation. Cancer Res, 1997, who found a 7.6-fold increased risk of benzene poisoning in workers carrying the TT genotype combined with CYP2E1 rapid metabolizer status. A subsequent PNAS study showed that TT homozygotes cannot induce NQO1 in response to hydroquinone exposure⁹⁹ cannot induce NQO1 in response to hydroquinone exposure
Moran JL, Siegel D, Ross D. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NQO1 to benzene toxicity. PNAS, 1999, leaving them unable to mount the normal protective enzyme response. Further studies in benzene-exposed workers found that those with the TT genotype who smoked or drank alcohol had 8- to 21-fold increased risk of benzene poisoning¹⁰¹⁰ 8- to 21-fold increased risk of benzene poisoning
Wan J et al. Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning. Environ Health Perspect, 2002.

Cancer risk: A comprehensive meta-analysis of 92 studies encompassing 21,178 cases and 25,157 controls¹¹¹¹ 92 studies encompassing 21,178 cases and 25,157 controls
Lajin B, Alachkar A. The NQO1 polymorphism C609T and cancer susceptibility: a comprehensive meta-analysis. Br J Cancer, 2013 found a statistically significant association between the TT genotype and overall cancer risk (OR 1.18, 95% CI 1.07-1.31). The strongest association was with bladder cancer (TT vs CC: OR 1.70, 95% CI 1.17-2.46). Notably, the association was more pronounced in Caucasian populations (OR 1.28) than in Asian populations, despite the much higher variant frequency in East Asians.

Breast cancer and chemotherapy: A Nature Genetics study¹²¹² Nature Genetics study
Fagerholm R et al. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet, 2008 found that NQO1*2 homozygosity strongly predicted poor survival in two independent series of breast cancer patients, with the effect particularly evident after anthracycline-based chemotherapy. This reflects NQO1's dual role in drug activation and p53 stabilization.

CoQ10 recycling: NQO1 is one of at least five enzyme systems that reduce ubiquinone to its active antioxidant form, ubiquinol. In individuals lacking functional NQO1, this recycling pathway is impaired. Preliminary evidence suggests that plasma CoQ10 levels may be lower in NQO1*2 carriers¹³¹³ plasma CoQ10 levels may be lower in NQO1*2 carriers
Ross D, Siegel D. Functions of NQO1 in Cellular Protection and CoQ10 Metabolism. Front Physiol, 2017, though larger confirmatory studies are needed.

Practical Implications

The TT (AA) genotype is especially relevant for individuals with occupational chemical exposures, those undergoing chemotherapy, and anyone interested in optimizing antioxidant status. Key considerations:

Chemical exposures: Individuals with the AA genotype should be particularly cautious about benzene and quinone-generating compound exposure. Benzene is found in gasoline, industrial solvents, and cigarette smoke. Minimizing exposure is more important when your body cannot efficiently detoxify the resulting quinone metabolites.

CoQ10 supplementation: Because NQO1 is one of the major enzymes that recycles CoQ10 from its oxidized (ubiquinone) to its reduced (ubiquinol) form, individuals with impaired NQO1 activity should use the ubiquinol form of CoQ10 rather than ubiquinone, as they may have reduced capacity to make this conversion themselves.

Antioxidant support: Without efficient quinone detoxification, the body experiences higher baseline oxidative stress. Supporting other antioxidant pathways -- through diet rich in colorful fruits and vegetables, and adequate selenium, vitamin C, and vitamin E -- becomes more important.

Oncology relevance: The NQO1 genotype may be relevant for chemotherapy drug selection, particularly for quinone-based agents and anthracyclines. This is an area of active research and should be discussed with an oncologist if relevant.

Interactions

NQO1 interacts with other Phase II detoxification and antioxidant enzymes. SOD2 (rs4880) converts superoxide to hydrogen peroxide, while NQO1 prevents superoxide generation in the first place by bypassing the semiquinone step. When both NQO1 and SOD2 are impaired, oxidative stress burden compounds -- NQO1 deficiency allows more superoxide generation, and SOD2 variants reduce the capacity to neutralize it.

GSTP1 (rs1695) is another Phase II enzyme that conjugates reactive metabolites with glutathione. Combined impairment of NQO1 and GSTP1 may further reduce the body's capacity to handle quinone toxicity and electrophilic compounds.

GPX1 (rs1050450) encodes glutathione peroxidase 1, which neutralizes hydrogen peroxide. In combination with NQO1 loss, reduced GPX1 activity creates a situation where both the generation of reactive oxygen species (via quinone redox cycling) and their clearance (via peroxide reduction) are compromised.

The combined effect of NQO1 TT with CYP2E1 rapid metabolizer status on benzene toxicity is well-documented: CYP2E1 rapidly converts benzene to quinone metabolites while NQO1 deficiency prevents their safe detoxification, creating a metabolic funnel toward toxicity.