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NADPH helps protect the immune system, prevents anemia, and plays an important role in many reactions of the body. Read more below to learn more about NADPH and NADPH oxidase.

What Is NADPH?

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

NADH and NADP+ can make NADPH through an enzyme (mitochondrial transhydrogenase). Or, NADP+ can make NADPH by itself through NADP+ dependent enzymes in the cellular fluid (cytosol) or mitochondria [R].

NADPH Function

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

It has 3 main functions. It contributes to antioxidant systems and is used during reactions (acting as a substrate) for NADPH oxidase (NOX) to make reactive oxygen species [R, R].

Finally, it also acts as a reducing agent in reactions by donating electrons to be used in reactions, which include the formation of DNA, fatty acids, and steroids. For example, NADPH supplies electrons for the NADPH-cytochrome P450 oxidoreductase system activity. This system is involved in drug metabolism and steroid formation [R, R].

NADPH and NADPH Oxidase

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

https://www.ncbi.nlm.nih.gov/pubmed/27174022

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

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

NOX is a major source of ROS in biological systems. Under normal conditions, the processes are sometimes beneficial and necessary for life; however, under abnormal conditions, they can be very harmful [R].

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

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) NADPH Increases Antioxidants

NADPH increases the amount of antioxidants in the body [R].

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

NADPH also plays important roles in two other antioxidant systems (thioredoxin and catalase) [R].

Increased NADPH levels protects against oxidative stress and cell death [R].

2) NADPH Helps Prevent Anemia

NADPH is essential in protecting against oxidative stress in red blood cells (erythrocytes). They that transports oxygen and carbon dioxide to and from the tissues [R].

A lack of NADPH can cause hemolysis, or the rupturing of red blood cells. Without NADPH,  membrane damage occurs [R].

Glucose-6-phosphate dehydrogenase (G6PD) converts NADP+ into NADPH. During G6PD deficiency, there is not enough NADPH. This makes red blood cells more susceptible to reactive oxygen species, which may cause anemia, spontaneous abortions, and problems with fetuses [R].

3) NADPH Oxidase Protects the Immune System

By generating free radicals in immune cells, NADPH oxidase helps destroy pathogens through a respiratory burst, which is when neutrophils (white blood cells) rapidly consume oxygen [R].

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 against the infectious threat [R].

Neutrophils require NOX to protect the body from Aspergillus fumigatus (fungus) and Burkholderia cepacia (bacteria) [R].

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

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

Negative Effects of NADPH and NADPH Oxidase

1) NADPH Contributes to Cancer Growth

Various tumors rely on NADPH for cell survival and function. By disabling pathways that convert NADP+ to NADPH, we can diminish tumor growth [R].

In a mouse model of skin cancer, NADPH production through the folate pathway helped cancer cells survive and promoted the spreading of cancer throughout the body [R, R].

2) NADPH Oxidase Harms the Brain

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 it contributes to cell death and brain dysfunction [R, R].

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

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

NOX activity can also 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 [R].

3) NADPH Oxidase May Contribute to Anxiety and Depression

Since NADPH oxidase can cause oxidative stress, this means that it also plays a role in anxiety. High oxidative stress levels are positively associated with anxiety [R].

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 [R].

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 [R].

In mice, long-term (chronic) stress also increased NOX activity and promoted depressive behavior (in social interactions). Inhibiting NOX produced antidepressive effects in the mice [R].

4) NADPH Oxidase May Increase Pain Sensitivity

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

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

Reactive oxygen species from NOX4 also contributed to nerve injury-related pain [R].

5) NADPH Oxidase May Harm Skin Health

NOX-produced reactive oxygen species helped keep the skin healthy and at a balance (homeostasis). The reactive oxygen species is crucial for skin and wound healing [R].

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

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 the spreading of cancer [R].

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 [R, R].

6) NADPH Oxidase 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 worsens insulin resistance and inflammation in fat cells [R].

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

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

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

7) NADPH Oxidase Has Conflicting Roles in Heart Health

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

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

However, in mice, NOX4 limited plaque accumulation. The genetic deletion of NOX4 enzymes rapidly increased atherosclerosis development [R].

8) NADPH Oxidase Both Protects and Harms Gut Health

NADPH oxidase generates reactive oxygen species in the gut to maintain balance (homeostasis) and to defend against pathogens. Patients with low NOX levels are more susceptible to bacterial and fungal infections. NOX-deficient mice could not defend against bacteria (Salmonella Typhimurium) colonization [R].

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 [R, R].

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

9) NADPH Oxidase and 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 [R].

People who have a mutation that causes DUOX2 inactivation will be more susceptible to extremely low thyroid hormone levels (congenital hypothyroidism) [R].

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

10) NADPH and Rheumatoid Arthritis

T cells are a type of white blood cells. The T cells of rheumatoid arthritis patients have high NADPH levels due to defects in the glycolysis pathway and PFKFB3 suppression [R].

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

11) NADPH Oxidase and Bone Health

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) [R].

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

12) NADPH Oxidase and Obesity

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

The reactive oxygen species that the NOX4 enzyme produces plays an important part 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 [R].

However, in a different study, NOX4 production increased in diet-induced obese rats. The increase in the enzyme is a response to obesity. It is currently unclear the exact role that NOX enzymes play in obesity [R].

13) NADPH Oxidase and Kidney Health

There are a lot of NADPH oxidase enzymes 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) [R].

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

Ways to Increase or Decrease NADPH

What Increases NADPH

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

  • 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 fungus [R].

Overproduction of the enzymes SIRT3 and/or IDH2 may increase levels of NADPH. This protects against oxidative stress and cell death. This may be a link to stopping the cancerous tumors [R].

What Decreases NADPH

  • High amounts of Vitamin C (in human cancer cells) [R, R]
  • tert-Butyl hydroperoxide (in rat livers) [R]
  • Paraquat (in rat livers) [R]

There are also various NOX enzyme inhibitors. Some specifically inhibit NOX enzymes, while others have unspecific effects [R]:

  • Apocynin
  • Diphenylene iodonium (DPI)
  • AEBSF
  • Plumbagin

There are also many NOX inhibitors currently still in research [R].

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

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 [R].

Other SNPs include [R, R]:

  • 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)

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