PHYSIOLOGY OF G6PD
ot only is it important to learn about the molecular biology of G6PD, but also the physiology of G6PD is important as well. The function of the normal G6PD enzyme is critical to human survival.
The G6PD enzyme catalyzes an oxidation/reduction reaction. Oxidation/reduction reactions function in transferring electrons from one molecule to another; oxidation is the loss of electrons and reduction is the gain of electrons. As illustrated in figure 3, the G6PD enzyme functions in catalyzing the oxidation of glucose-6-phosphate to 6-phosphogluconate, while concomitantly reducing nicotinamide adenine dinucleotide phosphate (NADP+ to NADPH); or, in terms of electron transfer, glucose-6-phosphate loses two electrons to become 6-phosphogluconate and NADP+ gains two electrons to become NADPH. This is the first step in the pentose phosphate pathway. This pathway, or shunt, as it is sometimes called, produces the 5- carbon sugar, ribose, which is an essential component of both DNA and RNA. There are other metabolic pathways, however, that can produce ribose if there is a deficiency in G6PD (Yoshida & Beutler, 1986).
In addition to producing the 5-carbon sugar ribose, G6PD is also responsible for maintaining adequate levels of NADPH inside the cell. NADPH is a required cofactor in many biosynthetic reactions. NADPH is also used to keep glutathione, a tri-peptide, in its reduced form (see Figure 3 ). Reduced glutathione acts as a scavenger for dangerous oxidative metabolites in the cell; it converts harmful hydrogen peroxide to water with the help of the enzyme, glutathione peroxidase (Yoshida & Beutler, 1986). There are other metabolic pathways that can generate NADPH in all cells, except in red blood cells where other NADPH-producing enzymes are lacking (Scriver et al., 1995).This has a profound effect on the stability of red blood cells since they are especially sensitive to oxidative stresses in addition to having only one NADPH-producing enzyme to remove these harmful oxidants. This is why G6PD deficient individuals are not prescribed oxidative drugs, such as those listed in Table 2, because the red blood cells in these individuals are not able to handle this stress and consequently hemolysis ensues.
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CLINICAL ASPECTS OF G6PD DEFICIENCY
CLINICAL ASPECTS OF G6PD DEFICIENCY
hen the red blood cell can no longer transport oxygen effectively throughout the body, a condition called hemolytic anemia arises. In addition to hemolytic anemia, G6PD deficient individuals can expect several other clinical manifestations of their condition. These include neonatal jaundice, abdominal and/or back pain, dizziness, headache, dyspnea (irregular breathing), and palpitations (Cecil, 1992). Only neonatal jaundice and hemolytic anemia will be discussed here, since these are the two major pathologies associated with G6PD deficiency (see Cecil, 1992, and Scriver et al., 1995, for a discussion of the other clinical manifestations of G6PD deficiency).
NEONATAL JAUNDICE
One of the problems experienced by G6PD deficient individuals presents itself immediately after birth. Neonatal jaundice is a common condition in all newborns, but when it persists, G6PD deficiency is suspected. Neonatal jaundice is a yellowish discoloration of the whites of the eyes, skin, and mucous membranes caused by deposition of bile salts in these tissues. This is a direct result of insufficient activity of the G6PD enzyme in the liver. In some cases, the neonatal jaundice is severe enough to cause death or permanent neurologic damage (Beutler, 1994).
HEMOLYTIC ANEMIA
Hemolytic anemia is another condition which may cause problems for G6PD deficient individuals. An anemic response can be induced in affected individuals by certain oxidative drugs, fava beans, or infections (Beutler, 1994). Death ensues if the hemolytic episode is not properly treated. In order to prevent a severe reaction or even death, G6PD deficient individuals are prohibited from taking certain drugs; a list of drugs that are commonly reported in the literature as inducing hemolysis in G6PD deficient individuals appears in Table 2. The common theme shared among all of these drugs is that they are oxidizing agents.In G6PD deficient individuals, oxidative stress may result in the denaturation, or unfolding, of the hemoglobin molecule, the principal oxygen carrying molecule inside the red blood cell. This results in the loss of biological function with respect to hemoglobin and leads to the inability of the red blood cell to effectively transport oxygen throughout the body (Yoshida & Beutler, 1986). For reasons still unknown, some G6PD deficient individuals do not exhibit drug-induced hemolytic anemia when exposed to certain drugs on this list; of course, a physician should always be consulted before any medications are taken.
Primaquine, one of the first anti-malarial drugs, was the first drug to be implicated in inducing an anemic response (Carson et al., 1956). All known anti-malarial drugs are contra-indicated for G6PD deficient individuals (see Table 2); however, in cases of acute uncomplicated malaria, most anti-malarial drugs can be safely administered (Baird, personal correspondence). It is interesting to note that a deficiency in G6PD has been shown to sometimes confer a resistance to the malaria-causing parasite, Plasmodium falciparum (Scriver et al., 1995). This resistance is due to the fact that the parasite selectively infects red blood cells. In G6PD deficient red blood cells, an essential metabolite for the survival of the parasite is present in insufficient quantities. This is due to decreased activity of G6PD within these cells which ultimately leads to the death of the parasite (Farid, personal interview).
In addition to drug-induced hemolytic anemia, there is also fava bean- induced hemolytic anemia--called favism. Fava beans were the first, and only food product, to be implicated in inducing an anemic response in G6PD deficient individuals (Scriver et al., 1995). Inhaling the pollen of the fava bean plant can also induce hemolysis in favic individuals. Since some G6PD deficient individuals are allergic to fava beans, the deficiency is therefore sometimes referred to as favism (THE FAVISM HOMEPAGE). Favism has been known to exist since antiquity; the Greek philosopher and mathematician Pythagoras was said to have warned his disciples against the dangers of eating fava beans (Scriver et al., 1995). The compounds vicine and isouramil, abundant in fava beans, are hypothesized to be the causative agents of the hemolytic response (Beutler, 1994).
Outside the areas where favism is prevalent, infection is probably the most common cause of hemolysis in subjects with G6PD deficiency. Oxidative metabolites produced by numerous bacterial, viral, and rickettsial infections have been identified as the cause of the anemic response. Particularly important infections that can precipitate a hemolytic episode are viral hepatitis, pneumonia, and typhoid fever (Cecil, 1992).
TREATMENT
Treatments for neonatal jaundice and hemolytic anemia have existed for many years. These treatments insure that the body tissues will be provided with enough oxygen by the red blood cells. Infants with prolonged neonatal jaundice are placed under special lights, called bili-lights, which alleviate the jaundice (Farid, personal interview). When an anemic episode occurs, individuals are treated with nasal oxygen and are placed on bed rest, which may afford symptomatic relief (Cecil, 1992). Anemic individuals are sometimes treated with human haptoglobin products (Ohga et al., 1995), and/or blood transfusions (Cecil, 1992). In acute hemolytic anemia, patients are administered folic acid (Cecil, 1992).
Soon, G6PD deficient individuals will no longer have to worry about incurring a hemolytic episode in response to fava beans. Techniques are currently being developed to genetically engineer the fava bean so that the hypothesized causative agents of the hemolytic response are eliminated from the bean. This is especially significant since fava beans are an important part of the diet in the Middle East, where the frequency of G6PD deficiency and favism is high
hen the red blood cell can no longer transport oxygen effectively throughout the body, a condition called hemolytic anemia arises. In addition to hemolytic anemia, G6PD deficient individuals can expect several other clinical manifestations of their condition. These include neonatal jaundice, abdominal and/or back pain, dizziness, headache, dyspnea (irregular breathing), and palpitations (Cecil, 1992). Only neonatal jaundice and hemolytic anemia will be discussed here, since these are the two major pathologies associated with G6PD deficiency (see Cecil, 1992, and Scriver et al., 1995, for a discussion of the other clinical manifestations of G6PD deficiency).
NEONATAL JAUNDICE
One of the problems experienced by G6PD deficient individuals presents itself immediately after birth. Neonatal jaundice is a common condition in all newborns, but when it persists, G6PD deficiency is suspected. Neonatal jaundice is a yellowish discoloration of the whites of the eyes, skin, and mucous membranes caused by deposition of bile salts in these tissues. This is a direct result of insufficient activity of the G6PD enzyme in the liver. In some cases, the neonatal jaundice is severe enough to cause death or permanent neurologic damage (Beutler, 1994).
HEMOLYTIC ANEMIA
Hemolytic anemia is another condition which may cause problems for G6PD deficient individuals. An anemic response can be induced in affected individuals by certain oxidative drugs, fava beans, or infections (Beutler, 1994). Death ensues if the hemolytic episode is not properly treated. In order to prevent a severe reaction or even death, G6PD deficient individuals are prohibited from taking certain drugs; a list of drugs that are commonly reported in the literature as inducing hemolysis in G6PD deficient individuals appears in Table 2. The common theme shared among all of these drugs is that they are oxidizing agents.In G6PD deficient individuals, oxidative stress may result in the denaturation, or unfolding, of the hemoglobin molecule, the principal oxygen carrying molecule inside the red blood cell. This results in the loss of biological function with respect to hemoglobin and leads to the inability of the red blood cell to effectively transport oxygen throughout the body (Yoshida & Beutler, 1986). For reasons still unknown, some G6PD deficient individuals do not exhibit drug-induced hemolytic anemia when exposed to certain drugs on this list; of course, a physician should always be consulted before any medications are taken.
Primaquine, one of the first anti-malarial drugs, was the first drug to be implicated in inducing an anemic response (Carson et al., 1956). All known anti-malarial drugs are contra-indicated for G6PD deficient individuals (see Table 2); however, in cases of acute uncomplicated malaria, most anti-malarial drugs can be safely administered (Baird, personal correspondence). It is interesting to note that a deficiency in G6PD has been shown to sometimes confer a resistance to the malaria-causing parasite, Plasmodium falciparum (Scriver et al., 1995). This resistance is due to the fact that the parasite selectively infects red blood cells. In G6PD deficient red blood cells, an essential metabolite for the survival of the parasite is present in insufficient quantities. This is due to decreased activity of G6PD within these cells which ultimately leads to the death of the parasite (Farid, personal interview).
In addition to drug-induced hemolytic anemia, there is also fava bean- induced hemolytic anemia--called favism. Fava beans were the first, and only food product, to be implicated in inducing an anemic response in G6PD deficient individuals (Scriver et al., 1995). Inhaling the pollen of the fava bean plant can also induce hemolysis in favic individuals. Since some G6PD deficient individuals are allergic to fava beans, the deficiency is therefore sometimes referred to as favism (THE FAVISM HOMEPAGE). Favism has been known to exist since antiquity; the Greek philosopher and mathematician Pythagoras was said to have warned his disciples against the dangers of eating fava beans (Scriver et al., 1995). The compounds vicine and isouramil, abundant in fava beans, are hypothesized to be the causative agents of the hemolytic response (Beutler, 1994).
Outside the areas where favism is prevalent, infection is probably the most common cause of hemolysis in subjects with G6PD deficiency. Oxidative metabolites produced by numerous bacterial, viral, and rickettsial infections have been identified as the cause of the anemic response. Particularly important infections that can precipitate a hemolytic episode are viral hepatitis, pneumonia, and typhoid fever (Cecil, 1992).
TREATMENT
Treatments for neonatal jaundice and hemolytic anemia have existed for many years. These treatments insure that the body tissues will be provided with enough oxygen by the red blood cells. Infants with prolonged neonatal jaundice are placed under special lights, called bili-lights, which alleviate the jaundice (Farid, personal interview). When an anemic episode occurs, individuals are treated with nasal oxygen and are placed on bed rest, which may afford symptomatic relief (Cecil, 1992). Anemic individuals are sometimes treated with human haptoglobin products (Ohga et al., 1995), and/or blood transfusions (Cecil, 1992). In acute hemolytic anemia, patients are administered folic acid (Cecil, 1992).
Soon, G6PD deficient individuals will no longer have to worry about incurring a hemolytic episode in response to fava beans. Techniques are currently being developed to genetically engineer the fava bean so that the hypothesized causative agents of the hemolytic response are eliminated from the bean. This is especially significant since fava beans are an important part of the diet in the Middle East, where the frequency of G6PD deficiency and favism is high
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