Downsides to the Nitrate–Nitrite– Nitric Oxide Pathway in Physiology And

Correspondence L i n k to O r i g i n a l a rt i c l e L i n k to A uthor’s rep ly

Finally, Lundberg and colleagues also alluded to the potential downsides to the Downsides to the nitrate–nitrite– therapeutic side of the pathway, including carcinogenesis (from nitrosoamines) and nitric oxide pathway in physiology methaemoglobinaemia1. As mentioned above, endocrine disruption by way of steroid defi- and therapeutics? ciency is another potential drawback8. The administration of nitrite and nitrate ions at levels allowable by the European Union in Nirmal Singh Panesar drinking water (50 mg per litre) significantly reduced the circulating levels of corticoster- In their recent Review article (The nitrate– steroid hormone synthesis, indicating that one and testosterone in rats5. In addition, the nitrite–nitric oxide pathway in physiology nitrate, and to a greater extent nitrite ions, adrenal glands of treated animals contained and therapeutics. Nature Rev. Drug Discov. 7, inhibit steroidogenesis in vitro and in vivo4,5 via lipid droplets similar to congenital adrenal 156–167 (2008))1, Lundberg and colleagues NO, as the NO scavenger carboxy-2-phenyl- hyperplasia due to some steroidogenic describe the concept of the nitrate–nitrite– 4,4,5,5,-tetramethylimidazoline-1-oxyl 3- enzyme deficiencies9. This possibility of nitric oxide (NO) pathway in physiology oxide (cPTIO) reversed the inhibition. It is endocrine disruption due to steroid hormone and therapeutics. However, there are some most likely that NO inhibits steroidogenesis deficiency should not be neglected when con- issues that merit consideration with regard by binding haem in steroidogenic cytochrome sidering the therapeutic potential of targeting to its physiological and pharmacological P450 enzymes. All these in vitro experiments the nitrate–nitrite–NO pathway. significance. with Leydig cells were done using buffers Nirmal Singh Panesar, Ph.D., is at the Department First, the authors are proponents of nitrite as with the prevailing 5–6 mg per litre dissolved of Chemical Pathology, The Chinese University an NO donor under severe hypoxic conditions, oxygen, a level that allows aquatic animals to of Hong Kong, Shatin, New Territories, Hong Kong. and according to REF. 1, this mechanism, as survive in water6. Therefore, the requirement e-mail: [email protected] mediated by deoxyhaemoglobin, should oper- for hypoxia to bioactivate nitrite to NO is 1. Lundberg, J. O., Weitzberg, E. & Gladwin, M. T. ate maximally at 50% haemoglobin saturation questionable. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nature Rev. Drug Discov. 7, (P50). However, although this state may exist Third, if the nitrate–nitrite–NO pathway 156–167 (2008). momentarily in metabolically active tissues operates, then the production of NO, the 2. Millar, T. M. et al. Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under such as the heart, it must be appreciated that vasodilator, should indeed be perpetual, with hypoxic conditions. FEBS Lett. 427, 225–228 (1998). the pulmonary venous haemoglobin saturation l-arginine-NO synthase producing it when 3. Cosby, K. et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. is usually around 75% (pO2 ≈ 40 mm Hg). oxygen is abundant, and the former pathway Nature Med. 9, 1498–1505 (2003). Second, it is also not certain that hypoxic activated under hypoxic conditions. However, 4. Panesar, N. S. Role of chloride and inhibitory action of inorganic nitrate on gonadotropin-stimulated conditions are a prerequisite for nitrite bio- this raises the question of why there is a need steroidogenesis in mouse Leydig tumor cells. activation to NO. Although it is thought that for therapeutic NO donors in patients with Metabolism 48, 693–700 (1999). 5. Panesar, N. S. & Chan, K. W. Decreased steroid xanthine oxidoreductase (XOR) performs its angina. Cardiac ischaemia should create a P50 hormone synthesis from inorganic nitrite and nitrate. surrogate “nitrite reductase” role in hypoxic state, and with ample blood nitrite (perhaps Studies in vitro and in vivo. Toxicol. Appl. Pharmacol. 2 3 169, 222–230 (2000). conditions , Gladwin and colleagues , who some arising from the damaged cardiac tissue), 6. Hodge, L. Environmental Pollution (Holt, Rinehart and reported pO2 values of around 20 mm Hg the pathway should generate enough NO to Winston, New York, 1973). 7. MacArthur, P. H., Shiva, S. & Gladwin, M. T. during exercise, were surprised that nitrite alleviate angina. Could it be that there is no Measurement of circulating nitrite and S-nitrosothiols infusion caused vasodilation in the absence blood nitrite for the purpose, because all of by reductive chemiluminescence. J. Chromatogr. B 851, 93–105 (2007). of “hypoxia and low pH”, a finding that chal- it has been metabolized? Indeed, there is 8. Pelley, J. Nitrate eyed as endocrine disrupter. Environ. lenged the XOR mechanism. That nitrite is controversy regarding blood nitrite concen- Sci. Tech. 37, 162A (2003). 9. White, P. C., New, M. I. & Dupont B. Congenital adrenal bioactivated to NO under aerobic conditions trations, which have been reported to range hyperplasia. N. Engl. J. Med. 316, 1519–1524 7 is perhaps illustrated by research related to from undetectable to 26 µM . (1987).