HERBICIDE-INDUCED EXPERIMENTAL VARIEGATE PORPHYRIA IN MICE - TISSUE PORPHYRINOGEN ACCUMULATION AND RESPONSE TO PORPHYROGENIC DRUGS

Administration of oxadiazon or oxyfluorfen (1000 ppm in the diet) to m ale BALB/c mice for 9 days resulted in experimental porphyria, resembl ing the acute phase of human variegate porphyria. Urinary concentratio ns of 5-aminolevulinic acid and porphobilinogen reached 1500 and 3000 mu mol/L, respectively. Both herbicides caused a decrease of protoporp hyrinogen oxidase activity in liver and kidney. Brain protoporphyrinog en oxidase activity was not altered. Liver and kidney porphyrin conten t increased to 11 and 17 nmol/g, respectively (control mice, 2 nmol/g) . Over 50% of liver and kidney porphyrins were in the reduced (porphyr inogen) form. Bile of oxadiazon-treated mice contained 700 nmol/ml of protoporphyrinogen (control mice, 15 nmol/mL). Porphyrin content of th e trigeminal nerve increased from 1 nmol/g in control animals to 11 nm ol/g in oxadiazon-treated animals, suggesting a possible contribution of peripheral nerve porphyrins to porphyric neuropathy. Mice treated w ith 125 ppm of oxadiazon in the diet for 9 days excreted moderately el evated levels of porphobilinogen in urine (control mice, less than 50 mu mol/L; treated mice, 330 mu mol/L). Administration of phenobarbital or phenytoin (single injections on days 7, 8, and 9) increased the ur inary porphobilinogen concentration to 3500 mu mol/L. This response to porphyrogenic drugs resembles the response observed in human acute po rphyrias.