Freeman J J, Hayes E P
J Toxicol Environ Health. 1985;15(5):609-21. doi: 10.1080/15287398509530690.
The purpose of these studies was to investigate the nature and mechanism of a toxicologic interaction between acetonitrile and acetone. Results of oral dose-response studies utilizing a 1:1 (w/w) mixture of acetonitrile and acetone, or varying doses of acetonitrile administered together with a constant dose of acetone, indicated that acetone potentiated acute acetonitrile toxicity three- to fourfold in rats. The onset of severe toxicity (manifested by tremors and convulsions) was delayed in the groups dosed with both solvents compared to the groups that received acetonitrile or acetone alone. Blood cyanide (a metabolite of acetonitrile) and serum acetonitrile and acetone concentrations were measured after oral administration of 25% aqueous solutions of acetonitrile, acetone, or acetonitrile plus acetone. Concentrations of cyanide in the blood of rats given acetonitrile plus acetone remained near baseline, in contrast to the high concentrations found in rats dosed with acetonitrile alone. At 34-36 h, high blood cyanide concentrations were found in rats dosed with both of the solvents. This delayed onset of elevation of blood cyanide coincided with the occurrence of clinical signs and with the disappearance of serum acetone. In further pharmacokinetic studies, blood cyanide concentrations were measured after similar dosage regimens of acetone and acetonitrile. Peak cyanide concentrations were found to be significantly greater in rats dosed with both solvents than in rats given only acetonitrile. Administration of either sodium thiosulfate or a second dose of acetone prevented the toxicity associated with exposure to both solvents. These results suggest that the effects of acetone on acetonitrile toxicity are due to a biphasic effect on the metabolism of acetonitrile to cyanide, that is, an initial inhibition followed by a stimulation of this metabolism upon acetone elimination.
这些研究的目的是调查乙腈和丙酮之间毒理学相互作用的性质和机制。利用乙腈和丙酮1:1（w/w）混合物进行口服剂量反应研究的结果，或不同剂量乙腈与恒定剂量丙酮联合给药的结果表明，丙酮可使大鼠急性乙腈毒性增强三至四倍。与单独接受乙腈或丙酮的组相比，同时给予两种溶剂的组严重毒性（表现为震颤和惊厥）的发作延迟。在口服乙腈、丙酮或乙腈加丙酮的25%水溶液后，测量血氰化物（乙腈的一种代谢产物）以及血清乙腈和丙酮浓度。与单独给予乙腈的大鼠中发现的高浓度相比，给予乙腈加丙酮的大鼠血液中的氰化物浓度保持在基线附近。在34 - 36小时时，同时给予两种溶剂的大鼠血液中发现高浓度的血氰化物。血氰化物升高的这种延迟发作与临床症状的出现以及血清丙酮的消失相一致。在进一步的药代动力学研究中，在给予丙酮和乙腈的类似给药方案后测量血氰化物浓度。发现同时给予两种溶剂的大鼠的氰化物峰值浓度显著高于仅给予乙腈的大鼠。给予硫代硫酸钠或第二剂丙酮可预防与暴露于两种溶剂相关的毒性。这些结果表明，丙酮对乙腈毒性的影响是由于对乙腈代谢为氰化物具有双相作用，即最初的抑制作用，随后在丙酮消除后对这种代谢产生刺激作用。
