NADPH, like NADH, can be considered a molecule with high energy. However, instead of being transferred to the electron transport chain like NADH, the electrons of NADPH are utilized for reductive biosynthesis. This is particularly observed in the metabolic processes of the pentose phosphate pathway, where a portion of the energy from glucose 6-phosphate is conserved in NADPH. NADPH, having a negative reduction potential, is capable of serving as an electron donor in reactions that require it, such as the synthesis of fatty acids, cholesterol, and steroid hormones.

The reduction of hydrogen peroxide (H2O2) is an important process since it is a reactive oxygen species (ROS) generated during aerobic metabolism, interactions with drugs and toxins, or when antioxidant levels are diminished. ROS, including H2O2, can cause severe damage to DNA, proteins, and unsaturated lipids, ultimately leading to cell death. Moreover, ROS has been implicated in various pathological conditions, including reperfusion injury, cancer, inflammatory diseases, and aging. To counteract the harmful effects of ROS, cells have several protective mechanisms.

One such protective mechanism involves the action of antioxidant enzymes. Reduced glutathione (GSH), a tripeptide-thiol found in most cells, can chemically detoxify H2O2. This reaction is facilitated by the selenoprotein glutathione peroxidase, which converts GSH into oxidized glutathione (G-S-S-G), thereby losing its protective properties. The cell then regenerates GSH through the activity of glutathione reductase, which utilizes NADPH as a source of reducing equivalents. Therefore, NADPH indirectly provides the necessary electrons for the reduction of H2O2. Additionally, other enzymes like superoxide dismutase and catalase aid in converting other ROS into harmless substances, collectively serving as a defense system against the toxic effects of ROS.

Apart from antioxidant enzymes, there are also antioxidant chemicals that can reduce and detoxify ROS. Ascorbate, vitamin E, and β-carotene are examples of intracellular reducing agents that have the ability to quench ROS in laboratory settings. Consumption of foods rich in these antioxidant compounds has been associated with a reduced risk of certain cancers and other chronic health problems. However, clinical trials using dietary supplements of antioxidants have not consistently shown clear beneficial effects. In fact, in the case of β-carotene supplementation in smokers, the rate of lung cancer increased rather than decreased. Therefore, the health benefits derived from dietary fruits and vegetables likely stem from a complex interaction among various naturally occurring compounds, which cannot be replicated by isolated antioxidant compounds.
Like NADH, NADPH can be thought of as a high-energy molecule. However, the electrons of NADPH are used for reductive biosynthesis, rather than for transfer to the electron transport chain as is seen with NADH (see p. 74). Thus, in the metabolic transformations of the pentose phosphate pathway, part of the energy of glucose 6-phosphate is conserved in NADPH, a molecule with a negative reduction potential (see p. 76), that, therefore, can be used in reactions requiring an electron donor, such as fatty acid (see p. 186), cholesterol (see p. 221), and steroid hormone (see p. 237) synthesis.
B. Hydrogen peroxide reduction
Hydrogen peroxide (H2O2) is one of a family of reactive oxygen species (ROS) that are formed from the partial reduction of molecular oxygen ([O2], Fig. 13.5A). These compounds are formed continuously as byproducts of aerobic metabolism, through reactions with drugs and environmental toxins, or when the level of antioxidants is diminished, all creating the condition of oxidative stress. These highly reactive oxygen intermediates can cause serious chemical damage to DNA, proteins, and unsaturated lipids and can lead to cell death. ROS have been implicated in a number of pathologic processes, including reperfusion injury, cancer, inflammatory disease, and aging. The cell has several protective mechanisms that minimize the toxic potential of these compounds. [Note: ROS can also be generated in the killing of microbes by white blood cells (WBC; see D. below).]
B. Actions of antioxidant enzymes. G-SH = reduced glutathione; G-S-S-G = oxidized glutathione. [Note: See Fig. 13.6B for the regeneration of G-SH.] 1. Enzymes that catalyze antioxidant reactions Reduced glutathione (GSH), a tripeptide-thiol (γ-glutamylcysteinylglycine) present in most cells, can chemically detoxify H2O2 (Fig. 13.5B). This reaction, catalyzed by the selenoprotein (see p. 407) glutathione peroxidase, forms oxidized glutathione (G-S-S-G), which no longer has protective properties. The cell regenerates G-SH in a reaction catalyzed by glutathione reductase, using NADPH as a source of reducing equivalents. Thus, NADPH indirectly provides electrons for the reduction of H2O2 (Fig. 13.6).
Additional enzymes, such as superoxide dismutase and catalase, catalyze the conversion of other ROS to harmless products (see Fig. 13.5B). As a group, these enzymes serve as a defense system to guard against the toxic effects of ROS.
glutathione.
2. Antioxidant chemicals A number of intracellular reducing agents, such as ascorbate (see p. 381), vitamin E (see p. 395), and β-carotene (see p. 386), are able to reduce and, thereby, detoxify ROS in the laboratory. Consumption of foods rich in these antioxidant compounds has been correlated with a reduced risk for certain types of cancers as well as decreased frequency of certain other chronic health problems. Therefore, it is tempting to speculate that the effects of these compounds are, in part, an expression of their ability to quench the toxic effect of ROS. However, clinical trials with antioxidants as dietary supplements have failed to show clear beneficial effects. In the case of dietary supplementation with β-carotene, the rate of lung cancer in smokers increased rather than decreased. Thus, the health-promoting effects of dietary fruits and vegetables likely reflect a complex interaction among many naturally occurring compounds, which has not been duplicated by consumption of isolated antioxidant compounds.