Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Abstract

Bromate is frequently detected in tap water and bottled water, since it is an inorganic oxyhalide disinfection by-product, which is formed when drinking water supplies undergo ozonation, an advanced wastewater treatment technique. 1,2) Potassium bromate (KBrO 3 ) is a renal carcinogen and is classified as a group 2B (possibly carcinogenic to humans) by the International Agency for Research on Cancer, 3,4) as are bleomycin and carbon tetrachloride, etc. However, KBrO 3 is generally used as an oxidizing agent for the treatment of wheat flour and as a constituent in cold-wave hair solutions. Acute exposure to KBrO 3 causes not only kidney failure 5,6) but also neuropathological disorder, such as vertigo, tinnitus, and hearing loss. 7,8) Potassium bromate is known to cause oxidative modification of lipid, protein and DNA bases in the kidney, which has usually been thought to contribute to its renal carcinogenic properties.9,10) Methaemoglobinemia and cyanosis in the incipient stage of renal damage are also known to be caused by KBrO 3 .11) Acquired but not heritable methaemoglobinemia is thought to be caused by the oxidative modification of haemoglobin (Hb) by certain chemicals, such as amyl nitrite and acetanilide, since the iron in the haem rings of Hb is in the Fe 2ϩ state and Hb oxidation is speeded up by the presence of nitrite or certain transition metal ions, especially copper.12) So far, KBrO 3 has been regarded as the direct oxidant of Hb as chlorate 13) but no details of KBrO 3 -induced elevation of methaemoglobin (MetHb) concentration in blood have been examined. Previously KBrO 3 -induced renal oxidative stress and kidney damage were reported to be mainly attributable to the reduction of cytoplasmic glutathione peroxidase (GPx) activity, probably caused by the enhanced production of NO and peroxynitrite (ONOO Ϫ ).14) Therefore, it is possible that KBrO 3 -induced methaemoglobinemia is also related to the change in GPx activity resulting from the enhancement of NO production in blood vessels. In this report, the effects of the GPx mimic ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) on the elevation of MetHb concentration, the enhancement of NO production and the attenuation of GPx activity by KBrO 3 are examined to clarify the significant impact of NO on KBrO 3 -induced methaemoglobinemia. In addition, the effect of ebselen on KBrO 3 -induced renal oxidative stress and kidney damage was comparatively investigated. MATERIALS AND METHODS ChemicalsGlutathione reductase from bakers yeast (EC 1.6.4.2), nitrate reductase from aspergillus species (EC 1.6.6.2), Hb, MetHb, reduced glutathione (GSH) and oxidized glutathione were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). 2,4-Dinitrophenylhydrazine (DNPH) was obtained from Tokyo Chemical Industry Co. (Tokyo, Japan). KBrO 3 , potassium cyanide, sodium hydrosulfite and ebselen were purchased from Wako Pure Chemical Industries (Osaka, Japan). 1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7), 3-(4-morpholinyl) sydnonimine hydroc...

Molecular mechanisms regarding potassium bromate‑induced cardiac hypertrophy without apoptosis in H9c2 cells

“…In the present study, KBrO3 at concentrations <250 µM induced cardiac hypertrophy without apoptosis in a cultured cell line. Additionally, it was demonstrated that free radicals and/or oxidative stress were mediated by the effect of KBrO3, which is fully consistent with previous reports that KBrO3 induces damage via oxidative stress (10)(11)(12). Cardiac injury induced by KBrO3 has also been observed in rats (15,16), and histological evidence demonstrates that KBrO3 induces cardiac apoptosis and/or necrosis in rodents (33).…”

“…Therefore, KBrO3 induced cardiac hypertrophy in H9c2 cells. ROS produced by KBrO3 are proposed as the primary mediators in tissue damage (11,16). Thus, the changes in ROS and superoxide levels were investigated.…”

“…Potassium bromate (KBrO3) has been widely used as a food additive and is also a by-product of disinfecting drinking water by ozonization (10). KBrO3 is applied primarily due to its oxidizing properties and may cause lipid peroxidation and oxidative DNA damage in humans and other mammals (11). KBrO3 is also known as a rodent carcinogen (12,13) and as a renal and/or neuro-toxicant in humans (14).…”

Potassium bromate causes cell lysis and induces oxidative stress in human erythrocytes

“…KBrO 3 caused a dramatic increase in MetHb formation at all concentrations used. Watanabe et al () have also reported increased MetHb levels in the plasma of mice that were orally administered bromate. Significantly, we have found that the activity of MetHb reductase, enzyme involved in the conversion of MetHb back to Hb, was increased showing that elevated levels of MetHb are not due to inhibition of this enzyme.…”

Protective effects of melatonin and indole‐3‐propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney

“…In fact, certain antioxidant substances, e.g., ebselen 11 or melatonin, 12 have already been shown to protect against oxidative damage, caused by KBrO 3 . Melatonin (N-acetyl-5-methoxytryptamine)-the pineal hormone-is an effective antioxidant and free radical scavenger.…”