Modulation of CYP4502E1 and oxidative stress by testosterone in liver and kidney of benzene treated rats.

Bilateral castration increased lipid peroxidation and consequently reduced glutathione in both liver and kidney. Testosterone administration reduced lipid peroxidation in the liver of castrated and benzene treated rats, however, reduced glutathione status could not be restored. Benzene depleted CYP4502E1 in castrated rats, however, the enzyme was restored in liver and kidney both after testosterone treatment. The results suggest that testosterone affects the metabolism and disposition of benzene by influencing CYP4502E1. Other hormonal and cellular/molecular factors may also alter the actions of testosterone. Testosterone dependent mechanism of toxicity of benzene in the liver and kidney has been discussed.

Molecular markers of heavy metal toxicity--a new paradigm for health risk assessment.

Last decade has witnessed increased interest in studies dealing with molecular markers of health and disease expression of genes. Specific toxicant "signatures" have been detected using genome base technologies such as microarrays. Further toxins have been classified on the basis of these signatures. Knowledge on these signatures has helped in the identification of novel drug candidates. This review discusses the gene expression studies recently made on arsenic, cadmium, mercury, chromium, lead, copper, nickel, manganese, and other essential elements. Toxicogenomics standards and their organizations have also been briefly described. Although this information can not be considered as complete, recent reports from different laboratories on bacteria, fish, laboratory animals and humans have been summarized. It is expected that toxicogenomics data presented in this review will be helpful in planning and excretion of human health risk assessment programs.

Amelioration of arsenic toxicity by L-Ascorbic acid in laboratory rat.

A study so as to confirm the protective effects of L-ascorbic acid against inorganic arsenic (As23) toxicity was made in male Wistar rats. Multiphase observations made on iAs concentration in target organs viz. liver and kidney, liver function, histopathological changes, ultrastructural alterations, lipid peroxidation, oxidative stress and iAs-DNA interaction strongly favoured its ameliorative effects. These effects could mainly be attributed to its antioxidative property. It offers help in regeneration of GSH and alpha-tocopherol. The chelaticn of iAs by ascorbic acid has also been hypothesized. Inhibition of DNA damage by ascorbic acid in liver and kidney appears to be the most significant part of this study On the basis of these results, we conclude that administration of L-ascorbic acid to arsenic affected population may prevent the occurrence of fatal human diseases.

Protective effect of ascorbic acid against oxidative stress induced by inorganic arsenic in liver and kidney of rat.

Ascorbic acid treatment in arsenic trioxide treated rats increased arsenic excretion, inhibited lipid peroxidation, improved GSH status, regulated GSSG turnover and also restored glutathione-S-transferases activity in liver and kidney. Suitable mechanisms leading to ascorbic acid protection have been discussed. Upregulation of GSH dependent enzymes was found to be necessary for a protective effect. Protection is finally attributed to higher GSH levels observed in the liver and kidney of ascorbic acid and inorganic arsenic treated rats. It is also concluded that ascorbic acid protection is influenced by gender dependent factors. Arsenic poisoning is a global problem now. Gender differences need to be considered while applying therapeutic measures.

Circadian variation in lipid peroxidation induced by benzene in rats.

Time-dependent effect of benzene, a potent carcinogenic industrial solvent, on lipid peroxidaiton and associated mechanisms has been studied in liver and kidney of rats. Significant differences were observed in the values of urinary phenol, microsomal malondialdehyde, reduced glutathione (GSH) and cytochrome P4502E1 in rats treated with benzene in morning and evening hours. Higher were the values for urinary phenol and hepatic microsomal malondialdehyde in rats administered benzene in evening hours. Contrarily, higher were the values for GSH and cytochrome P4502E1 in rats treated with benzene in morning hours. Increased microsomal lipid peroxidation has been attributed to low GSH status, whereas increased phenol concentration could be related to low activity of cytochrome P4502E1 in the liver of rats in evening hours. It is concluded that circadian rhythmicity in hepatic drug metabolizing enzyme system and GSH contributes in toxicity of benzene. The results are important from occupational health point of view.

Biochemical toxicity of benzene.

Human exposure to benzene in work environment is a global occupational health problem. After inhalation or absorption, benzene targets organs viz. liver, kidney, lung, heart and brain etc. It is metabolized mainly in the liver by cytochrome P450 multifunctional oxygenase system. Benzene causes haematotoxicity through its phenolic metabolites that act in concert to produce DNA strand breaks, chromosomal damage, sister chromatid exchange, inhibition of topoisomerase II and damage to mitotic spindle. The carcinogenic and myelotoxic effects of benzene are associated with free radical formation either as benzene metabolites or lipid peroxidation products. Benzene oxide and phenol have been considered as proheptons. Liver microsomes play an important role in biotransformation of benzene whereas in kidney, it produces degenerative intracellular changes. Cohort studies made in different countries suggest that benzene induces multiple myeloma in petrochemical workers. Though extensive studies have been performed on its toxicity, endocrinal disruption caused by benzene remains poorly known. Transgenic cytochrome P450 IIE1 mice may help in understanding further toxic manifestations of benzene.

Sex differences in oxidative stress induced by benzene in rats.

Role of sex differences on oxidative stress induced by benzene has been studied in liver, kidney and lungs of rat. It was observed that benzene administration enhanced lipid peroxidation in liver, kidney and lungs of rat, nevertheless, significant variations were recorded in male and female rats. Decrease of GSH and CYTP(450)2E1 was higher in female rats than male rats except lungs. The results suggest that oxidative stress induced by benzene is higher in female rats.

Gender differences in the metabolism of benzene, toluene and trichloroethylene in rat with special reference to certain biochemical parameters.

Metabolites viz. phenol, hippuric acid and total trichloro compounds of benzene, toluene and trichloroethylene respectively were estimated in the urine samples of male and female rats after exposure for a period of 30 days. The results exhibited higher metabolism in female rats than the male rats. Their metabolism might be regulated by cytochrome P450 isozymes in a gender specific manner. However, sex differences in the activity of glutathione-S-transferases of the liver have also been found to determine their toxicity. Results have been discussed with quantitative profiles of other enzymes established in the liver of male and female rats.

Inevitable glutathione, then and now.

Glutathione a predominant tripeptide thiol compound of many prokaryotes and eukaryotes, is synthesized from its precursor amino acids eg. gamma-glutamate, cysteine and glycine. It is mainly involved in detoxication mechanisms through conjugation reactions. Other functions include thiol transfer, destruction of free radicals and metabolism of various exogenous and endogenous compounds. It becomes mandatory for a cell to manage high concentration of intracellular GSH to protect itself from chemical/dug abuse. Glutathione dependent enzymes viz: glutathione-S-transferases, glutathione peroxidase, glutathione reductase and gamma-glutamate transpeptidase facilitate protective manifestations. Liver serves as a glutathione-generating factor which supplies the kidney and intestine with other constituents of glutathione resynthesis. The principal mechanism of hepatocyte glutathione turnover appears to be cellular efflux. Kidney too plays an important role in organismic GSH homeostasis. Role of GSH in organs like lung, intestine and brain has recently been described. GSH involvement in programmed cell death has also been indicated. Immense interest makes the then "thee glutathione" as "inevitable glutathione". This article describes the role of this vital molecule in cell physiology and detoxication mechanisms in particular.

Free radical scavenging and metal chelation by Tinospora cordifolia, a possible role in radioprotection.

Aqueous extract of T. cordifolia inhibited Fenton (FeSO4) reaction and radiation mediated 2-deoxyribose degradation in a dose dependent fashion with an IC50 value of 700 microg/ml for both Fenton and radiation mediated 2-DR degradation. Similarly, it showed a moderate but dose dependent inhibition of chemically generated superoxide anion at 500 microg/ml concentration and above with an IC50 value of 2000 microg/ml. Aqueous extract inhibited the formation of Fe2+-bipiridyl complex and formation of comet tail by chelating Fe2+ ions in a dose dependent manner with an IC50 value of 150 microg/ml for Fe2+-bipirydyl formation and maximally 200 microg/ml for comet tail formation, respectively. The extract inhibited ferrous sulphate mediated lipid peroxidation in a dose-dependent manner with an IC50 value of 1300 microg/ml and maximally (70%) at 2000 microg/ml. The results reveal that the direct and indirect antioxidant actions of T. cordifolia probably act in corroboration to manifest the overall radioprotective effects.