The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals: consequences for occupational and environmental medicine.

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/ RsaI (mutant allele: CYP2E1*5B) located in the 5'-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

[The effect of sodium thiosulfate on nonspecific body resistance and on the immune reactions in acute acrylonitrile poisoning]. / Vliianie tiosul'fata natriia na nespetsificheskuiu rezistentnost' organizma i immunnye reaktsii pri ostrom otravlenii akrilonitrilom.

Experiments on noninbred Wistar mice and rats showed that acute acrylonitrile (0.5 LD50) intoxication leads to decrease of nonspecific resistance of the organism and humoral and cellular immunity responses. The antidote sodium thiosulfate increases suppression of the responses under study.

Acute acrylonitrile toxicity: studies on the mechanism of the antidotal effect of D- and L-cysteine and their N-acetyl derivatives in the rat.

Thiol-containing antidotes for acute acrylonitrile (AN) toxicity may exert their action by chemically reacting with AN, by replacing critical sulfhydryl groups cyanoethylated by AN, and by detoxifying cyanide produced from AN metabolism. We have evaluated the ability of the optical isomers of cysteine and N-acetylcysteine to act as antidotes against AN toxicity in order to assess the relative importance of each of these three antidotal mechanisms. The toxicity of AN was determined in male Sprague-Dawley rats and compared to the toxicity determined after treatment with 2 mmol/kg of thiol antidote by computing a protective index (median lethal dose with antidote/median lethal dose without antidote). The protective indices of L-cysteine, D-cysteine, N-acetyl-L-cysteine, and N-acetyl-D-cysteine were 2.03, 1.97, 1.76, and 1.25, respectively. Measurements of urinary mercapturates, derived from the non-oxidative pathway of AN metabolism, indicated that none of the antidotes was able to significantly increase the excretion of these metabolites. Blood cyanide generated from the oxidative metabolism of AN and butyronitrile was also determined. All of the antidotes, except N-acetyl-D-cysteine, lowered blood cyanide levels. A comparison of these results with the predicted relative abilities of the enantiomers to participate in each of the three antidotal mechanisms leads to the conclusion that, under these experimental conditions, the best correlation exists with the cyanide detoxification mechanism.

[Use of antioxidants for preventing the hepatotoxic effect of acrylonitrile]. / Ispol'zovanie antioksidantov dlia preduprezhdeniia gepatotoksicheskogo éffekta akrilonitrila.

The authors examined the possibility of using antiooxidants in the chemoprophylaxis of poisonings with alkylating chemical compounds. It was demonstrated that vitamin E, ionol and low-molecular thiols (cystein, glutatione and unithiol) prevent the increased permeability of plasma membranes and impairment of the protein-synthesizing function of the endoplasmic reticulum of hepatoytes in acute and chronic acrylonitrile poisoning.

[Effect of ascorbic acid and B group vitamins on the course of subacute acrylonitrile poisoning in rats]. / O vliianii askorbinovoi kisloty i nekotorykh vitaminov gruppy B na techenie podostroi intoksikatsii nitrilom akrilovoi kisloty u krys.

The effect of ascorbic acid and a mixture of pyridoxine and nicotinamide on the process of subacute poisoning with acrylonitrile (AN) in a concentration of 9.7 +/- 2.8 mg/m3 (corresponding to the threshold of a chronic action) was studied in rats. Administration of an additional mixture of vitamins had no significant effect on the course of subacute poisoning in rats. Changes in the physiological and biochemical parameters characteristic of the AN poisoning were noted in this group of animals at the end of the experiment. No significant changes were observed in the poisoning of rats after an additional administration of ascorbic acid either at the stage of the initial reactions, or at the end of the experiment. The results obtained indicate a strongly pronounced elevation of the adaptibility of the organism. This allows one to regard ascorbic acid as an alimentary factor of protective action in repeated subacute AN poisoning of the organism. Ascorbic acid can be recommended as a prophylactic agent for persons in continuous contact with AN under industrial conditions.

[Effect on the body of rats of rations varying in protein content in acrylomitrile poisoning]. / Izuchenie vliianiia na organizm krys razlichnykh po soderzhaniiu belka ratsionov pri intoksikatsii nitrilom akrilovoi kisloty.

The effect of protein of isocaloric rations (10, 18 and 30 per cent of the total calorific value) differing in its proportion on the course of a subacute poisoning provoked by the acrylic acid nitrile (AAN) in a concentration of 9.7 +/- 2.8 mg/m3 was studied. A comparative study of the results obtained showed that a protein-rich ration produced a more pronounced protective effect. Against its background the AAN metabolites were eliminated from the organism more intensively. This effect could have been occasioned by an excessive supply to the organism together with the additional protein of free sulphur and of SH-group necessary for rendering the cyanides harmless. Considering the results obtained and with the view of a more effective prevention of the AAN poisoning it is advisable to recommend providing workers with a protein-rich medico-prophylactic ration containing an assortment of food products rich in sulphur-containing elements.

[Experimental evaluation of therapeutic-prophylactic nutrition in exposure to acrylonitrile]. / K otsenke lechebno-profilakticheskogo pitaniia pri vozdeistvii nitrila akrilovoi kisloty v éksperimente.

The purpose of the work was to study the prophylactic effect of a synthetic complete ration with an addition of L-cysteine in doses of 300 and 150 mg/kg and also investigation of the protective action exerted by 3 rations with varying content of protein (10, 18 and 30 per cent) and calorific value with a repeated and chronic inhalation of AAN in concentrations of 20 +/- 5 and 9 +/- 2.8 mg/m3. The effectiveness of the food rations under study was evaluated basically according to metabolic criteria. The metabolic indices were found to be the most sensitive ones and changing early following the effect of AAN. For this reason they may serve as criteria for not only assessing the noxious action of the poison, but also in devising the type of the medico-prophylactic dietary.

[Protective action of sulfur-containing compounds in acrylonitrile poisoning]. / O zashchitnom deistvii serosoderzhashchikh soedinenii pri intoksikatsii nitrilom akrilovoi kisloty

Experiments staged on rats evidenced that from among sulfur-containing amino acids (methionine, cystine and cysteine) and sodium thiosulfate it was cysteine that displayed a pronounced prophylactic and therapeutic effect in acute mortal poisonings with acrylic acid nitrile.