K. Indira

Neurotoxicity of hexachlorophene in mice: Implications of altered cerebral amino acid profiles

Oral administration of hexachlorophene (HCP) produced neurotoxic symptoms in mice. Using high-pressure liquid chromatography, the profiles of the cerebral free amino acids of the control and HCP intoxicated mice were analyzed. There was a significant rise in the levels of the neutral amino acids glutamine, threonine, phenylalanine, leucine, isoleucine and valine. A rise in glutamine levels was most notable, and was associated with increased glutamine synthetase and decreased glutaminase activity levels. Concentrations of the acidic amino acids, aspartic acid and glutamic acid were significantly decreased. The γ-aminobutyric acid (GABA) levels were increased, while glutamic acid-to-glutamine and glutamic acid + aspartic acid-to-GABA ratios showed significant decrements in the brains of mice subjected to repeated HCP administration. The characteristic changes, particularly of transmitter amino acids, denoted a trend towards the depletion of excitatory amino acids and an accumulation of the inhibitory amino acid GABA, which might deserve consideration in the expression of neurologic symptoms in HCP intoxication.

Age-related changes in muscle ammonia detoxification potential in exhausted rats

The changes in the pattern of production and detoxification of ammonia have been studied in the skeletal muscles and blood of rats of different age groups (1, 3, 6, 12 and 24 months), subjected to exhaustive exercise. The protein profiles at exhaustion showed a sharp drop in all muscles and the decrement was more in the senile rats. In general, the muscle and blood ammonia content increased with age with a corresponding increase in AMP deaminase activity implicating the possibility of elevated purine nucleotide deamination during senescence. However, glutamate oxidation was decreased and urea and glutamine formation was increased consequent to ammonia production during senescence under intensive physical stress. The possible alterations in protein levels and ammonia production and its disposal in different skeletal muscle types of senile exhausted rats have been discussed in relation to detoxication capacity of the fibre types.

In vitro kinetics of the mouse hepatic arginase inhibition by hexachlorophene

Abstract Hexachlorophene (HCP) inhibited mouse hepatic arginase with a half-inhibitory concentration (I50) of 1.3 × 10−6 M. The enzyme-HCP interaction coefficients denoted alteration of inhibitory sites on the enzyme, depending on the concentration of HCP. The Km of hepatic arginase was 8.3 mM which was not significantly affected in the presence of HCP, whereas the Vmax and Vmax-to-Km ratios were reduced by HCP by the same factor, denoting a pure noncompetitive inhibition which was further confirmed by the finding that the inhibitor constants Ki and K′i were equal to one another and also to the I50. The enzyme in the presence of HCP demanded higher than the normal amount of activation energy (Ea). The Mn2+-activated arginase was less susceptible than was the Mn2+-deficient enzyme to HCP inhibition. These findings, together with recovery studies employing bovine serum albumin, denoted that HCP may induce conformational changes on the enzyme, probably by exerting strong interactions at the noncatalytic sites of the enzyme.

Brain ammonia metabolism in hexachlorophene-induced encephalopathy.

In spite of long and extensive use of hexachlorophene (HCP) as an antibacterial and antifungal agent in a wide variety of cosmetics, medical and home care products since 1949 (Gump & Walter 1968), it was only in 1971 that the toxic potential of this compound was recognized; mainly because of the HCP-induced neuropathologic changes observed by kimbrough et al. Since then, several studies concerned with the neurotoxic i ty of HCP have been conducted, however the biochemical mechanism of HCP action remained obscure. HCP is reported to exert toxic effects on non nervous tissues as well. Freeze fracture studies showed that administration of an acute dose of 30 mg HCP/kg causes disorganization in t ight junctions, increase in number of gap junctions and disruption of mitoehondria in the l iver of rats (Robenek et al. 1980). When HCP was given intragastrical ly at doses of 60 mg/kg/day for 1 week, mice exhibited degenerative changes in l iver (Prasad 1986). Since hepatic degeneration is most commonly associated with abnormal ammonia metabolism and brain function, an at tempt has been made in the present study to investigate the cerebral ammonia, glutamate and related metabolite patterns in mice during HCP-induced neurotoxici ty.

Catalytic potential of field mouse Mus booduga brain acetylcholinesterase during repeated hexachlorophene treatment

The catalytic efficiency of the field mouse (Mus booduga) brain acetyl cholinesterase (AChE, EC 3.1.1.7) was significantly (P less than 0.001) decreased probably through the reduction in the active site density of the enzyme content and elevation in the activation energy (delta E) requirements during repeated hexachlorophene (HCP) treatment. Fall in the activity potential of AChE may account for the interference of HCP or its reactive metabolites with the acetylcholine (ACh)-AChE system and deserve consideration in contributing to the neurotoxicity.

Influence of malathion on the catalytic potential of glutamate dehydrogenase in sheep brain

Abstract Malathion stimulated sheep brain glutamate dehydrogenase. The maximal velocity (V max ) and Michaelis-Menten constant ( K m ) showed alterations characteristic of nonessential activation. The activation energy required by the enzyme subjected to pesticidal stress was found to decrease, suggesting a decrement in energy barrier for the catalysis of the enzyme. The possible implications of malathion-stimulated glutamate dehydrogenase activity are discussed.

Inhibition of sheep brain acetylcholinesterase by hexachlorophene

Hexachlorophene (HCP) is a broad spectrum fungicide and bacteriocide (Nakaue et al. 1972) used as an anthelmintic agent in sheep (Hall and Reid 1972). HCP is neurotoxic and its neuropathology includes paralysis associated with edema and spongy degeneration of cerebral white matter (Lockhart 1972; Shuman et al. 1973). Since HCP is an established neurotoxicant, it is possible that neurotransmission could also be affected. As a majority of neurons in sheep brain are cholinergic in action, an attempt has been made in this study to assess the response of acetylcholinesterase (ACHE) to HCP treatment in vitro.

Ambient ammonia effect on catalytic potential of muscle and gill AMP deaminase in Fish

AMP deaminase activity was inhibited in gill and muscle of Sarotherodon mossambicus, subjected to a week-long exposure to sublethal concentration of ambient ammonia. pH-dependent kinetic studies revealed decreased catalytic efficiency of the enzyme due to altered active site density and ionization pattern in the fish tissues at different phases of ammonia exposure.

Sciatectomic Stimulation of Muscle Arginase and Its Implications

Denervated muscle is characterized by high turnover of proteins, hyperammonemia, degeneration and regeneration of muscle fibers (Shahzad, 1977; Goldspink 1978; Chetty et al, 1980). In view of these conditions an enzyme like arginase, which cleaves L-arginine to L-ornithine and urea was investigated mainly because, its detoxification role in ammoniotoxemia is well established and its role in extra hepatic tissues, where other urea cycle enzymes are absent, still remains to be elucidated.