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NADPH & NADPH Oxidase: Functions + Health Effects

Written by Carlos Tello, PhD (Molecular Biology) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Last updated:

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NADPH
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NADPH is a coenzyme that contributes to multiple biological reactions by supplying electrons. It helps protect the immune system, prevents anemia, and plays an important role in many reactions of the body. Read below to learn more about NADPH and NADPH oxidase.

What Is NADPH?

Nicotinamide adenine dinucleotide phosphate (NADPH) is a form of NADP+ [1].

NADH and NADP+ can make NADPH through an enzyme called mitochondrial transhydrogenase. Alternatively, NADP+ can make NADPH by itself through NADP+-dependent enzymes in the cellular fluid or the mitochondria [1].

Function

NADPH plays an important role in many biological processes, including energy metabolism, immune system function, cell aging, and cell death [1].

It has 3 main functions [2, 1, 3]:

  • Contributing to antioxidant systems
  • Acting as a substrate for NADPH oxidase (NOX) to make reactive oxygen species
  • Supplying electrons for several reactions including the formation of DNA, fatty acids, and steroids or the drug metabolism by the NADPH-cytochrome P450 oxidoreductase system activity

NADPH and NADPH Oxidase

NADPH oxidases (NOX) are enzymes present in many blood cells and involved in antibacterial and antifungal defense, as well as the autoimmune system. The NOX family includes 7 members: NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2 [4].

In cells that line the blood vessels, NOX makes reactive oxygen species (ROS) in response to cytokines, growth factors, stress, and G-protein-coupled receptors [2].

NOX transfers electrons from NADPH inside the cell across the membrane and binds them to oxygen to produce the superoxide anion. This generates other reactive oxygen species [4].

NOX is a major source of ROS in biological systems. Under normal conditions, the processes are sometimes beneficial and necessary for life (e.g., when ROS act as messenger molecules or help destroy pathogens); however, under abnormal conditions, they can be very harmful [4].

It is important for cells to prevent excessive NADPH supply to NOX, because NOX can contribute to various diseases, such as cancer, artery hardening (atherosclerosis), high blood pressure, and Alzheimer’s disease [5].

Most of NADPH’s health effects come from NOX transferring electrons from NADPH to make reactive oxygen species.

Health Benefits of NADPH and NADPH Oxidase

1) Increases Antioxidants

NADPH increases the antioxidant status of the body. It provides the electrons necessary for biological reactions that involve reduction (the opposite of oxidation) and protects the tissues against oxidative stress and cell death [2, 6].

The production of glutathione (GSH), an important antioxidant, requires NADPH. Some scientists think that NADPH plays a bigger role in antioxidant defense in red blood cells than GSH [1].

NADPH also plays important roles in the function of two other antioxidant systems: thioredoxin and catalase [1, 7, 8].

2) Helps Prevent Anemia

NADPH is essential in protecting against oxidative stress in red blood cells (erythrocytes), which transport oxygen and carbon dioxide to and from the tissues [9].

A lack of NADPH can cause hemolysis or the rupturing of red blood cells due to oxidative damage of the cell membrane. The lack of viable red blood cells causes anemia [10].

Glucose-6-phosphate dehydrogenase (G6PD) is needed to convert NADP+ into NADPH. In people with genetic G6PD deficiency, NADPH production is insufficient. This makes red blood cells more susceptible to reactive oxygen species, ultimately causing anemia, spontaneous abortions, and problems with fetuses [9].

3) Protects the Immune System

By generating free radicals in immune cells, NADPH oxidase helps destroy pathogens through a respiratory burst. In this process, neutrophils (a type of white blood cell) rapidly transform oxygen into reactive oxygen species [11].

NOX plays an important role in antimicrobial defense. Microbes and microbial-derived products activate NOX, which then assembles quickly and makes reactive oxidant intermediates (ROIs) to defend the organism against the infectious threat [11].

Neutrophils require NOX to protect the body from infectious microbes such as the fungus Aspergillus fumigatus and the bacteria Burkholderia cepacia, both of which can cause infections in people with a weakened immune system [12].

In other immune cells (macrophages and dendritic cells), NOX2’s roles are less clear. However, scientists believe that NOX2 helps limit chronic inflammation [13].

The effects of NOX activation on inflammation depends on the person and can either reduce or aggravate inflammation. Without NOX, excessive inflammation can cause frequent and harsh bacterial and fungal infections [11].

Negative Effects of NADPH and NADPH Oxidase

1) May Contribute to Cancer Growth

Various tumors rely on NADPH for cell survival and function. This suggests that the pathways that convert NADP+ to NADPH can be a therapeutic target for anticancer therapies [14].

In mice with skin cancer, NADPH production through the folate pathway helped cancer cells survive and promoted the spreading of cancer throughout the body [15, 16].

2) May Contribute to Brain Damage

NADPH oxidase (NOX) generates reactive oxygen species that cause oxidative stress and play a role in cognitive impairment. Most of its negative effects occur in age-related diseases, such as Alzheimer’s and Parkinson’s, as oxidative stress contributes to cell death and brain dysfunction [17, 18].

Scientists found increased NOX levels in brain autopsies of Alzheimer’s patients. Increased NOX activity is associated with early dementia, most likely as a result of oxidative stress [17].

In mice, NOX also contributed to oxygen deprivation (hypoxia)-related brain injury and excessive daytime sleepiness [19].

NOX activity has also been suggested to contribute to traumatic brain injury (TBI). In mice, apocynin (a NOX inhibitor) protected against brain injuries and reduced inflammatory cytokine (IL-1β, TNF-α) levels [20].

3) May Contribute to Anxiety and Depression

Since NADPH oxidase can cause oxidative stress, it may also play a role in anxiety. High oxidative stress levels are associated with anxiety [21].

BSO is a drug that induces oxidative stress. It caused anxious behavior in mice by activating the NOX pathway. Blocking the NOX pathway helped reduce oxidative-stress related anxiety [22].

In another mouse study, the NOX1 enzyme increased oxidative stress and disturbed NMDA receptor activity. This lowered the production of BDNF, which helped with stress adaptation. Reduced BDNF causes depressive behaviors [23].

In mice, long-term stress also increased NOX activity and promoted depressive behavior in social interaction). Inhibiting NOX produced antidepressive effects [24].

4) May Increase Pain Sensitivity

Reactive oxygen species are involved in pain signaling. The ROS from NOX1 play an important role in the development of increased sensitivity to pain (hyperalgesia). Mice lacking NOX1 had reduced pain during inflammation. Thus, blocking the NOX1 pathway may help reduce pain sensitivity [25].

Additionally, mice with nerve injuries had increased NOX2 levels in their spinal cord cells. This increased inflammatory cytokine (TNF-α and IL-1β) levels and contributed to nerve pain sensitivity [26].

Reactive oxygen species from NOX4 also contributed to pain due to nerve injury [27].

5) May Reduce Skin Health

NOX-produced reactive oxygen species helped keep the skin healthy and at a balance (homeostasis) in animal and cell-based studies. These free radicals are crucial for skin and wound healing [28].

However, improper ROS production can prolong the inflammatory response and impair the healing process. It also increases inflammatory markers (such as Nf-kB, IL-4, and IL-13), which contributes to psoriasis and eczema [28].

Additionally, NOX plays a role in skin aging and disease progression. NOX generates ROS after UV radiation exposure, which may cause inflammation, cell death, or tumor formation. NOX1 and NOX4 play important roles in skin cancer progression and spreading [28].

A review showed that various NOX inhibitors were able to reduce ROS production and, subsequently, tumor progression. A NOX1 inhibitor also reduced factors of premature skin aging (β-galactosidase activity, reactive oxygen species, and progerin levels) in mice [28, 29].

6) May Contribute to Diabetic Complications

In mice, during the early stages of obesity, NOX4-derived reactive oxygen species (from fat cells) caused insulin resistance. Later, in the intermediate stages, ROS from NOX2 worsened insulin resistance and inflammation in fat cells [30].

Inhibiting NOX2 in mice helped restore blood vessel function in insulin-resistant mice, which may prevent plaque buildup. In diabetic rats, apocynin (a NOX inhibitor) also helped prevent diabetes-induced kidney disease [31, 32].

NOX-produced ROS also damage the mitochondria in eye cells, causing diabetic eye disease (retinopathy) [33].

High glucose levels may induce NOX activity in the heart, causing oxidative stress and contributing to heart problems. However, the full roles of NOX enzymes in diabetes-induced heart disease are still unknown [34].

7) May Contribute to Rheumatoid Arthritis

The T cells of rheumatoid arthritis patients have high NADPH levels due to defects in the glycolysis pathway and PFKFB3 suppression [35].

NADPH converts glutathione disulfide into glutathione and diminishes reactive oxygen species (ROS) in the joint cells. Reduced ROS production is associated with increased joint inflammation severity [35].

8) May Contribute to Bone Loss

The body needs NOX4 activity for both osteoblast and osteoclast formation. Osteoblasts are cells that make proteins needed for bone formation, while osteoclasts destroy bone tissue. Both are needed for forming new bone and keeping balance (homeostasis) [36].

However, NOX increases reactive oxygen species formation, which increases inflammation. Both are risk factors for osteoporosis [36].

Dual (Both Positive and Negative) Effects of NADPH and NADPH Oxidase

1) Heart Health

NOX4 is present in the mitochondria of heart cells. Increased NOX4 enhances reactive oxygen species (ROS) production. Normally, ROS help with cell growth, survival, and metabolism. However, excessive ROS can lead to DNA and protein damage, organ dysfunction, and cell death [37].

Through oxidative stress and p53 activation, NOX activity induces various heart disease factors, including thickening of the heart muscles (hypertrophy), scarring of tissue (fibrosis), high blood pressure, hardening of the arteries (atherosclerosis), and cell death [37, 38, 39].

However, in a study in mice, NOX4 limited artery clogging. The genetic deletion of NOX4 enzymes rapidly increased atherosclerosis development [40].

2) Gut Health

NADPH oxidase generates reactive oxygen species in the gut to maintain balance (homeostasis) and to defend against pathogens. People with low NOX levels are more susceptible to bacterial and fungal infections. NOX-deficient mice were more susceptible to gut colonization by a microbe that causes diarrhea and vomiting (Salmonella typhimurium) [41].

Although NADPH oxidase is important for normal immune responses in the gut, it can also contribute to colon inflammation. NOX increases reactive oxygen species in the body, which contributes to tissue damage during inflammatory diseases, such as IBD. For example, IBD patients have increased Nox1 production [41, 42].

Additionally, NOX inhibitors protected mouse colon cells from inflammation [41].

3) Thyroid Function

Thyroid hormone formation requires hydrogen peroxide. DUOX2, an NADPH oxidase enzyme, produces most of the hydrogen peroxide for thyroid hormone formation. Two other NOX enzymes, DUOX1 and NOX4, both play roles in thyroid function, but their exact roles are currently unknown [43].

People with a mutation that causes DUOX2 inactivation may be more susceptible to extremely low thyroid hormone levels (congenital hypothyroidism) [43].

However, DUOX1, DUOX2, and NOX4 are overproduced in human thyroid tumors. DUOX1 production is also increased in radiation-induced thyroid cancer. Its hydrogen peroxide production promotes DNA damage in thyroid cells after radiation exposure [43].

4) Obesity

NADPH oxidase is a major contributor to oxidative stress in fat tissue [44].

The reactive oxygen species that the NOX4 enzyme produces play an important role in fat cell formation and insulin signaling. NOX4-deficient mice have accumulated fat tissue and are more likely to become obese. After eating a high-fat diet, the NOX-4 deficient mice had increased body weight, inflammation, and insulin resistance [45].

However, in a different study, NOX4 production was higher in diet-induced obese rats. The increase in the enzyme was a response to obesity. The exact role that the NOX enzymes play in obesity remains unclear [46].

5) Kidney Health

NADPH oxidase enzymes are very abundant in the kidneys. NOX-produced reactive oxygen species help with glucose production and transport. However, NOX2 and NOX4 can contribute to kidney damage, tissue scarring (fibrosis), and diabetic kidney disease (nephropathy) [47].

Inhibiting NOX enzymes in mice helped reduce kidney damage markers (albuminuria, fibrosis, and oxidative stress) [47].

Ways to Increase or Decrease NADPH

What Increases NADPH

The enzymes that contribute to NADPH generation include [1]:

  • Pentose phosphate pathway enzymes (G6DPH and 6GDH)
  • Isocitrate dehydrogenases (IDPc and IDPm)
  • Malic enzymes (MEPc and MEPm)
  • Mitochondrial transhydrogenase

Overproduction of glucose 6-phosphate dehydrogenase may increase NADPH concentration. However, this did not greatly affect NADPH levels in fungi [48].

Overproduction of the enzymes SIRT3 and/or IDH2 may increase levels of NADPH. This protects against oxidative stress and cell death [6].

What Decreases NADPH

  • High amounts of vitamin C (in human cancer cells) [14, 49]
  • tert-Butyl hydroperoxide (in rat livers) [50]
  • Paraquat (in rat livers) [50]

There are also various NOX enzyme inhibitors. Some specifically inhibit NOX enzymes, while others have non-specific effects [51]:

  • Apocynin
  • Diphenyleneiodonium (DPI)
  • AEBSF
  • Plumbagin

There are also many NOX inhibitors whose development is currently being investigated [51].

Additionally, histamine inhibits NOX2 activity in bone marrow cells [52].

Genes/SNPs

Normally, NOX1 generates reactive oxygen species in the gut to maintain balance (homeostasis) and protect against pathogens. However, defects in the NOX1 gene can cause the onset of inflammatory bowel disease (IBD). Two SNPs (rs34688635 and a new, unnumbered one) are associated with a higher risk for IBD [53].

Other SNPs include [54, 55]:

  • Rs11018628 in NOX4 is associated with reduced bone density (strength)
  • Rs4821544 in NCF4 is associated with increased risk for Crohn’s
  • Rs10911363 in NCF2 is associated with increased risk for lupus (SLE)

About the Author

Carlos Tello

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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