PubMed · 7153804
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W K Viscusi. 1982. Setting efficient standards for occupational hazards.. https://pubmed.ncbi.nlm.nih.gov/7153804/
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The cytochrome P450-mediated oxidation of acrylonitrile (ACN) to the mutagen 2-cyanoethylene oxide (CEO) is thought to be important for the carcinogenic effects of ACN in rats, while glutathione (GSH) conjugation of ACN and CEO is regarded as detoxication. A physiologically based dosimetry description for ACN and CEO in the male F-344 rat has been developed from in vitro data and studies of the iv pharmacokinetics of ACN and CEO. The dosimetry description includes tissue partition coefficients and in vitro estimates of the rates of reaction of ACN and CEO with hemoglobin and blood macromolecules and the reaction of CEO with tissue GSH. Metabolic parameters for ACN and CEO were estimated from iv pharmacokinetic studies. Rats were given bolus doses of 3.4, 47, 55, or 84 mg ACN/kg via the femoral vein and blood samples were collected at selected time points. ACN and CEO blood concentrations were determined by gas chromatography. The iv pharmacokinetics of CEO were also determined using 0.6 or 5.3 mg CEO/kg. ACN elimination from blood was described by saturable P450 epoxidation (Vmax of 6.5 mg/hr/kg and Km of 1.5 mg/liter) and first-order GSH conjugation (30 hr-1/kg). CEO elimination was described by first-order GSH conjugation (750 hr-1/kg). Calculation of hepatic clearance values shows first-pass hepatic extractions of 61 and 90% for ACN and CEO, respectively. The dosimetry description accurately simulated the dose-dependent urinary excretion of ACN metabolites derived from epoxidation to CEO and from direct GSH conjugation of ACN. The dose-dependent formation of hemoglobin adducts from ACN was also well simulated.
Acrylonitrile (VCN) is known to cause extensive gastrointestinal damage and tumors in rats. In this study the metabolism of VCN to cyanide (CN-) was characterized in the small intestinal mucosa. The majority of the metabolic reactivity was localized in the microsomal fraction and required reduced nicotinamide adenine dinucleotide phosphate for maximal activity. The intestinal metabolism of VCN to CN- was characterized with respect to VCN concentration, time, pH, and microsomal protein concentration. VCN metabolism to CN- was enhanced significantly by the addition of sulfhydryl compounds such as glutathione, cysteine, and D-penicillamine (10 mM) to 142, 161, and 189% of control, respectively. The intestinal bioactivation of VCN to CN- was enhanced by microsomes obtained from intestinal mucosa of phenobarbital (455% of control), beta-naphthoflavone (375% of control), 4-methylpyrazole (305% of control), or ethanol (165% of control)-treated rats. Addition of ethanol (80 mM) to incubation mixtures containing control or ethanol-induced microsomes resulted in significant inhibition of microsomal metabolism of VCN to CN- to 20 and 34% of control, respectively. Addition of dimethyl sulfoxide induced a similar inhibitory effect on VCN metabolism by control or ethanol-induced microsomes (8 and 26% of control, respectively). Furthermore, antibody to cytochrome P450 2E1, but not antibody to cyt P450 2B1, significantly inhibited VCN metabolism by ethanol-induced intestinal microsomes to about 25% of control. Mild inhibition (80-85% of control) of VCN metabolism was detected when antibody to cyt P450 2B1 or 2E1 was added to incubation mixtures containing Pb-induced intestinal microsomes. These findings indicate that extrahepatic tissues such as the intestinal mucosa are capable of metabolizing VCN to CN- and establish a major role of intestinal cyt P450, particularly cyt P450 2E1, in the intestinal metabolism of VCN to CN-.
The glutathione (GSH) conjugation of the rat carcinogen acrylonitrile (ACN) and its epoxide metabolite 2-cyanoethylene oxide (CEO) by rat, mouse, and human liver enzymes was characterized in vitro since GSH conjugation is the major disposition pathway for these chemicals in vivo. Mass spectral analyses indicated that S-(2-cyanoethyl)GSH was the product from reaction of GSH and ACN and that S-(cyanohydroxyethyl)GSH reaction products were formed from CEO. Because of the rapid nonenzymic reactions of ACN and CEO with GSH at pH 7.3, the steady-state kinetics of hepatic GSH conjugation were determined at pH 6.5 by HPLC analysis of the products. Hyperbolic kinetics were observed with respect to GSH for the reactions catalyzed by mouse or rat hepatic cytosols at pH 6.5, whereas sigmoidal kinetics were observed with respect to ACN or CEO. This kinetic pattern is consistent with the random sequential kinetic mechanism that has been described for GSH S-transferases. Estimates of the maximal velocities of the reaction at pH 6.5 showed that mouse enzymes had a 4- to 6-fold greater capacity for GSH conjugation of ACN and CEO than rat enzymes. ACN appeared to be conjugated with GSH more efficiently than CEO under these conditions. At physiological pH (7.3), rapid nonenzymic conjugation of GSH (10 mM) with ACN or CEO (5 mM) was observed (approximately 25 and 15 nmol product/min, respectively). Addition of hepatic cytosols or microsomes from rats or mice increased the velocity of GSH conjugation approximately 1.6-fold. A similar velocity enhancement was observed with human liver cytosols for the GSH conjugation of ACN, but not for CEO. Human liver microsomes did not enhance the velocity of GSH conjugation of either substrate. These results suggest that ACN is a better substrate for human liver GSH S-transferases than CEO. Estimation of the initial velocities of the GSH conjugation reactions in intact rodent liver from the in vitro data at pH 7.3 suggests that the enzyme-mediated GSH conjugation of ACN and CEO will be approximately 4-fold greater than the velocity of the direct chemical reaction with GSH.