What is the physiologic mechanism for reducing methemoglobin to its original ferrous state?

Updated: Dec 09, 2018
  • Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

The second and more important mechanism involves two enzyme systems, diaphorase I and diaphorase II, and requires nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), respectively, to reduce methemoglobin to its original ferrous state.

NADH-dependent methemoglobin reduction (diaphorase I pathway) is the major enzymatic system involved. [6] Cytochrome b5 reductase plays a major role in this process by transferring electrons from NADH to methemoglobin, an action that results in the reduction of methemoglobin to hemoglobin. This enzyme system is responsible for the removal of 95-99% of the methemoglobin that is produced under normal circumstances.

NADPH-dependent methemoglobin reduction (diaphorase II pathway) usually plays only a minor role in the removal of methemoglobin. This enzyme system utilizes glutathione production and glucose-6-phosphate dehydrogenase (G6PD) to reduce methemoglobin to hemoglobin. It assumes a larger and more important role in methemoglobin regulation in patients with cytochrome b5 reductase deficiencies.

The NADPH-dependent methemoglobin reduction pathway can be accelerated by exogenous cofactors such as methylene blue to as much as five times its normal level of activity. [3, 7, 6, 8] In the absence of further accumulation of methemoglobin, these methemoglobin reduction pathways can clear methemoglobin at a rate of approximately 15% per hour.

Acquired methemoglobinemia is considerably more common than congenital forms.


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