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Adaptation of Cytochrome-B5 Reductase Activity and Methaemoglobinaemia in Areas with a High Nitrate Concentration in Drinking-Water S.K

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Adaptation of Cytochrome-B5 Reductase Activity and Methaemoglobinaemia in Areas with a High Nitrate Concentration in Drinking-Water S.K Adaptation of cytochrome-b5 reductase activity and methaemoglobinaemia in areas with a high nitrate concentration in drinking-water S.K. Gupta,1 R.C. Gupta,2 A.K. Seth,3 A.B. Gupta,4 J.K. Bassin,5 & A. Gupta6 An epidemiological investigation was undertaken in India to assess the prevalence of methaemoglobinaemia in areas with high nitrate concentration in drinking-water and the possible association with an adaptation of cytochrome-b5 reductase. Five areas were selected, with average nitrate ion concentrations in drinking-water of 26, 45, 95, 222 and 459 mg/l. These areas were visited and house schedules were prepared in accordance with a statistically designed protocol. A sample of 10% of the total population was selected in each of the areas, matched for age and weight, giving a total of 178 persons in five age groups. For each subject, a detailed history was documented, a medical examination was conducted and blood samples were taken to determine methaemoglobin level and cytochrome-b5 reductase activity. Collected data were subjected to statistical analysis to test for a possible relationship between nitrate concentration, cytochrome-b5 reductase activity and methaemoglobinaemia. High nitrate concentrations caused methaemoglobinaemia in infants and adults. The reserve of cytochrome-b5 reductase activity (i.e. the enzyme activity not currently being used, but which is available when needed; for example, under conditions of increased nitrate ingestion) and its adaptation with increasing water nitrate concentration to reduce methaemoglobin were more pronounced in children and adolescents. Voir page 752 le reÂsume en francËais. En la pa gina 753 figura un resumen en espanÄ ol. Introduction only to their concentration in drinking-water and food, but also to conditions conducive to their Excessive nitrate concentration in drinking-water is reduction to nitrites. reported to have caused methaemoglobinaemia in When nitrates are ingested, reduction to nitrites infants up to 6 months of age (1±5). Maximum occurs in the intestinal tract, although some studies permissible limits for nitrate ion in drinking-water suggest that this may start in the oral cavity (8). Nitrite have been set at 50 mg/l by WHO (6) and 45 mg/l by ions are absorbed into the bloodstream where they the Bureau of Indian Standards (IS-10500) (7). In are converted back to nitrates. During this process, several developing countries, especially India, con- haemoglobin is converted to methaemoglobin. In sumption of water containing high nitrate concen- healthy individuals, absorbed nitrates are rapidly trations, sometimes as high as 500 mg/l, is not excreted by the kidney (9). uncommon. The essential action in the formation of In the body, nitrates are reduced to nitrites, methaemoglobin is the oxidation of the ferrous ion causing methaemoglobinaemia. The reduction usual- of haemoglobin to the ferric ion, which can be brought ly occurs through microbial action. The health risks about by the direct action of oxidants, by the action of from exposure to nitrates are therefore related not hydrogen donors in the presence of oxygen, or by auto- oxidation (10). In the presence of nitrites, oxidation is direct. Normally, the methaemoglobin that is formed is 1 Junior Specialist, Satellite Hospital, Banipark, Jaipur 302 006, India. reduced by the following reaction (11): 3+ 2+ Correspondence to this author at A 31-B, Anita Colony, Bajaj Nagar, Hb +reduced cytochrome b5 ? Hb +oxidized Jaipur 302 015, India. cytochrome b5. 2 Associate Professor, Department of Physiology, SMS Medical College, Reduced cytochrome b5 is regenerated by the Jaipur 302 004, India. enzyme cytochrome-b5 reductase: 3 Scientist and Head, Jaipur Zonal Laboratory, National Environmental Cytochrome-b Engineering Research Institute, CFC-1, Malviya Industrial Area, Jaipur 5 oxidized cytochrome b5+NADH ÐÐÐÐ? 302 017, India. reductase 4 Professor of Environmental Engineering, Malaviya Regional reduced cytochrome b5+NAD Engineering College, Jaipur 302 017, India. 5 Scientist, Jaipur Zonal Laboratory, National Environmental Thus, the enzyme cytochrome-b5 reductase plays a Engineering Research Institute, CFC-1, Malviya Industrial Area, Jaipur vital role in counteracting the effects of nitrate 302 017, India. ingestion. 6 Research Associate, Department of Physiology, SMS Medical College, Infants constitute a vulnerable group for a Jaipur 302 004, India. number of reasons (9): the higher pH of the stomach Ref. No. 0023 (2.0±5.0) permits the growth of nitrate-reducing Bulletin of the World Health Organization, 1999, 77 (9) # World Health Organization 1999 749 Research organisms (Escherichia coli, Salmonella spp. etc.); infants dance with the modified method of Evelyn & Malloy have a higher consumption of water per unit body (13). Cytochrome-b5 reductase activity (NADH- weight; fetal haemoglobin, present in infants up to dependent diaphorase activity, expressed as IU per 6 months of age, is more readily oxidized to gram of haemoglobin) was determined by the methaemoglobin than adult haemoglobin; and the methaemoglobin ferricyanide method (14). development of the NADH-methaemoglobin re- Collected data were subjected to correlation ductase system is incomplete. and regression analysis using Microsoft Excel soft- While a few cases of methaemoglobinaemia in ware to test for correlations between nitrate infants have been reported to be associated with concentration, cytochrome-b5 reductase activity and water nitrate levels of less than 50 mg/l, most cases methaemoglobinaemia. occur at levels of 90 mg/l or more (1±5, 12). The following clinical manifestations at different met- haemoglobin concentrations have been reported (9): Results at <10%, no signs and symptoms; at 10±25%, no symptoms, cyanosis present; at 26±50%, cyanosis, Drinking-water nitrate concentrations of 26, 45, 95, dyspnoea and headache; at 51±60%, dyspnoea even 222 and 459 mg/l, respectively, were found in the on lying, cyanosis and disorientation; and at >60%, five village units. The level of methaemoglobin and lethal consequences. average cytochrome-b5 reductase activity for the Despite the fact that, in several Indian villages, different age groups and nitrate concentrations are people have been consuming water containing high presented in Tables 1 and 2. Figures 1 and 2 show nitrate concentrations, at times up to 500 mg/l, no nitrate concentration versus methaemoglobin level studies have been conducted so far to ascertain the and average cytochrome-b5 reductase activity for the prevalence of clinically manifest methaemoglobinae- five age groups. mia in infants. An epidemiological investigation was Methaemoglobin levels were considerably therefore undertaken in these areas to assess higher than 2% of the total haemoglobin concentra- methaemoglobinaemia at different ages and to tion, the reported mean content of methaemoglobin examine the protective mechanism of cytochrome- in healthy populations (9). High levels of methaemo- globin were not restricted to infants only but were b5 reductase activity. also prevalent in older age groups. High values were observed in all age groups at all nitrate concentra- Materials and methods tions. Maximum levels were observed at 45±95 mg/l in all age groups, with the highest value in infants (age Water analysis was conducted in five selected village group 1). This peak was followed by a decline in units (a part of the village served by a single source of methaemoglobin and then another rising trend as drinking-water) in the State of Rajasthan, India, nitrate concentration increased. where high average nitrate concentrations were Clinical cyanosis was the main presentation in known to occur. Nitrate concentration was deter- age group 1 but it was also present in all other age mined using an ultraviolet spectrophotometric groups. Recurrent respiratory infection (40±82%) screening method (12). The selected village units and recurrent diarrhoea (33±55%) were found in were physically close to each other, lying within a groups 1 and 2 and recurrent stomatitis (17±24%) radius of 2 km. Other environmental, social and was observed in all age groups. nutritional conditions in the selected village units were similar. These village units were visited and house Statistical analysis schedules, recording details about family members, their name, age, sex, weight, etc., were prepared. A Age group 1 sample of 10% of the total population from each There was good correlation between cytochrome-b5 village unit, matched for age and weight, was selected reductase activity and methaemoglobin levels for detailed clinical and biochemical examination. A (0.5699). Cytochrome-b5 reductase activity showed total of 178 persons were selected in five age groups: an initial rising trend with increasing nitrate concen- 41 year of age (group 1), >1±48 years (group 2), tration and methaemoglobin levels but never ex- >8±418 years (group 3), >18 years±445 years ceeded 10 IU/g Hb, indicating a poor reserve of this (group 4), and >45 years of age (group 5). Infants activity in this age group. This may also account for below the age of three months could not be included the poor correlation between nitrate concentration as a separate group for medical and ethical reasons. and cytochrome-b5 reductase activity (0.1179) in this The number of parents willing to permit collection of age group, which has been reported by other workers blood samples from such infants was very small. also. With a further increase in nitrate concentration, For each subject, a detailed
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