Propionitrile: whole body autoradiography, conventional toxicokinetic and metabolism studies in rats

The toxicokinetics, covalent binding and metabolism of propionitrile (PCN) was investigated in female Sprague-Dawley rats. For toxicokinetic studies a tracer dose of 100 microCi/Kg (11.8 mumol/Kg) [2(-14)C] PCN was injected i.v. and selected animals were sacrificed 1, 8, and 24 h post administration. Within an hour of administration peak concentration of PCN-derived radioactivity was detected in duodenum, kidney, lung, large intestine, plasma, red blood cells, stomach, heart, and brain. The treated animals excreted about 5.3% of the dose in 24 h, with approximately equal amounts in the expired air and the urine with traces in the feces. Presence of PCN-derived radioactivity up to 24 hours in the gastrointestinal tract suggests an enterohepatic recirculation of PCN and/or its metabolites. The subcellular fractions of liver duodenum and brain showed significant (p < or = 0.05) accumulation of PCN-derived radioactivity. Nuclear fraction accumulated the highest amount of radioactivity in the liver. duodenum and brain. The data indicate that PCN is readily distributed in the rat, it is metabolized to cyanide via the cytochrome P-450-dependent mixed-function oxidase system and that the direct interaction of PCN and/or its metabolites with duodenal tissues appears to be the first step in the expression of its overall toxicity. This report also shows that, for limited chemicals, whole body autoradiography combined with computer-aided imaging techniques, provides a powerful approach to preliminarily evaluate the toxicokinetic behavior of xenobiotics very quickly.