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Drug Summary: Riboflavin acts as an integral component of two coenzymes: FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). These flavin coenzymes are critical for the metabolism of carbohydrates, fats, and proteins into energy. Because riboflavin is an important component of these flavin coenzymes, riboflavin supplementation is believed to increase the efficiency of energy metabolism in cells.

Riboflavin, also known as vitamin B2, is a water-soluble vitamin that is found naturally in the food we eat. Sources of riboflavin include organ meats (liver, kidney, and heart) and certain plants such as almonds, mushrooms, whole grain, soybeans, and green leafy vegetables.

In the body, riboflavin acts as an integral component of two coenzymes: FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). A coenzyme is a molecule required for the activity of another enzyme. FAD and FMN are known as flavins since they are derived from riboflavin. These flavin coenzymes are critical for the metabolism of carbohydrates, fats, and proteins into energy. Specifically, FAD and FMN are involved in the activity of the electron transport chain, an essential component of energy metabolism that is known to be impaired in people with HD. (For more on metabolism, link to HD and Energy Metabolism).

Fig J-1: Role of NAD/NADH

In the electron transport chain, FMN is one of the components of complex I while FAD is involved in the activity of complex II. FAD acts as an electron carrier and takes part in both the Kreb’s Cycle and oxidative phosphorylation. It accepts electrons and is transformed into FADH2. FADH2 then transfers its electrons to complex II of the electron transport chain. For each pair of electrons from FADH2 passed along the electron transport chain, a number of ATP molecules are formed. FAD also affects enzymes that are responsible for the synthesis of other vital coenzymes such as NAD. Severe deficiencies in riboflavin can lower levels of coenzymes, leading to inefficient energy metabolism and consequent energy depletion. Figure J-1 shows the roles of FAD and FMN in the electron transport chain.

Impaired energy metabolism has been found to be associated with the progression of HD. Because of the role of riboflavin derivatives in the electron transport chain, scientists are looking into the possibility of riboflavin supplementation as a way of improving energy metabolism. Researchers hope that improving energy metabolism will slow or even stop the progression of HD. However, as of this time (October 2001), most studies done on riboflavin supplementation have concentrated on people with energy deficits due to mitochondrial disorders, rather than people with HD. Some of the disease mechanisms of these mitochondrial disorders are similar to those of HD. Because of these similarities, studies on people with mitochondrial disorders may be of interest to people with HD as well.

Research on Riboflavin^

Bernsen, et al. (1993) evaluated the effects of riboflavin treatment in five (5) patients with mitochondrial myopathies. Mitochondrial myopathies are disorders often characterized by defects in the electron transport chain. Specifically, the participants in the study had a deficiency of Complex I, the largest of the electron transport chain enzymes.

Complex I removes electrons from NADH, an electron carrier, and passes them to ubiquinone. As mentioned above, complex I contains a flavin component, FMN, that is essential for the proper functioning of the complex. Riboflavin supplementation is hypothesized to improve the efficiency of the Complex I protein by increasing the concentrations of available FMN molecules in the cell.

Motor and muscle strength improvements, as well as lactate levels, were used by the researchers to measure the efficacy of riboflavin. Lactate levels are used by scientists as a measure of the efficiency of metabolism in the cell. In normal cells, a form of metabolism known as aerobic respiration is usually used for energy production. If aerobic respiration is impaired, such as in the case of people with HD and with mitochondrial disorders, cells switch to anaerobic respiration, a less efficient form of metabolism. Lactate is a by-product of anaerobic respiration and lactate levels indicate which form of metabolism is the primary form the cells use for its energy needs. High levels of lactate indicate low metabolism efficiency in that cells are “forced” to use anaerobic respiration. On the other hand, low levels of lactate indicate high metabolic efficiency in that aerobic respiration is the primary form of energy production.

Before treatment, the participants suffered from high lactate levels, exercise-induced weakness, muscle atrophy and other motor problems. Treatment with riboflavin resulted in varying degrees of improvement in three of the five patients. Two patients experienced no improvement, and the remaining three patients with improved conditions showed normalized lactate levels and improved muscle strength and motor abilities.

Ogle, et al. (1997) reported the effects of riboflavin in a case involving a female patient with a myopathy caused by Complex I deficiency. The patient had a mutation that caused instability in the assembly of the complex I protein and consequent deficiency in complex I activity. She suffered from frequent falls and could no longer climb the stairs due to muscle weakness. She also showed increased lactate levels.

Treatment with riboflavin during a 3-year period showed normalization in blood lactate levels. The participant was also able to walk longer distances and to rise from the floor without difficulty. An obvious worsening of symptoms occurred during one period when the participant failed to take riboflavin. Exercise tolerance deteriorated, muscle tone worsened, and lactate levels rose during the period when riboflavin was not used. The symptoms observed when riboflavin was not used suggest that the previous improvements were associated with riboflavin supplementation.

This case suggested that riboflavin may have beneficial effects on people with Complex I deficiencies.

For further reading^

  1. Bernsen, et al. “Treatment of complex I deficiency with riboflavin.” Journal of the Neurological Sciences. 1993; 118: 181-87.
    This article reports that riboflavin treatment may have beneficial effects in some people with mitochondrial myopathies.
  2. Matthews, et al. “Neuroprotective Effects of Creatine and Cyclocreatine in Animal Models of Huntington’s Disease.” The Journal of Neuroscience. 1998, 18: 156-163.
    This article reports the Creatine supplementation results in decreased nerve cell lesions often found in cells with energy depletion.
  3. Ogle, et al. “Mitochondrial myopathy with tRNA sup Leu(UUR) mutation and complex I deficiency responsive to riboflavin.” Journal of Pediatrics. Januargy 1997; 130(1): 138-145.
    This article reports that riboflavin supplementation may improve the conditions of people with Complex I deficiency.
  4. Riboflavin available online
    Contains information about the possible beneficial effects of riboflavin on a variety of diseases.

-E. Tan, 9-22-01