Experimental mycotoxic nephropathy in pigs provoked by a diet containing ochratoxin A and penicillic acid.

Mycotoxic nephropathy was induced in 18 young pigs by diets contaminated with strains of Aspergillus ochraceus containing ochratoxin A (OTA) and penicillic acid (PA) at levels corresponding to those naturally encountered in animal feeds in Bulgaria. Haematological and biochemical parameters, as well as the morphological and ultrastructural changes in various internal organs, and especially in the kidneys, were examined at different stages of development of the disease. A mottled surface of the kidneys was only seen in pigs exposed to a mouldy diet containing 180 ppb OTA for 3 months, but microscopic lesions, as well as changes in various haematological and biochemical parameters, were observed in all groups exposed to the same mouldy diet containing only 90 or 180 ppb OTA. Histological examination showed two types of change: degenerative changes affecting the epithelial cells of the proximal tubules, which predominated at the initial stage, and proliferative changes in the interstitium, which predominated at the later stage of the disease. Telangiectasis and lymph stasis were also seen, as well as degenerative changes in the capillary endothelium. The characteristic renal lesions were similar to those observed in spontaneous cases of mycotoxic porcine nephropathy in Bulgaria, but they were a little different from the classic Danish porcine nephropathy. The enhanced toxicity of OTA in our study may be due to a synergistic effect between OTA and PA or to some other unknown metabolites produced by the same ochratoxinogenic strains of A. ochraceus.

Pharmacokinetics of the mycotoxin penicillic acid in male mice: absorption, distribution, excretion, and kinetics.

The pharmacokinetics of penicillic acid (PA), a carcinogenic mycotoxin, was investigated in male mice. Absorption of PA after po administration of [14C]PA was rapid. Only a small percentage of the radioactivity in the plasma was unchanged PA. After ip or iv administration of [14C]PA (90 mg/kg), blood, liver, kidneys, intestine, lungs, heart, and spleen contained the largest amounts of radioactivity while brain tissue accumulated the least. Over 90% and approximately 60% of the administered radioactivity was excreted in the urine after iv and ip injection, respectively, but essentially no unchanged PA was detected in the urine. Over 25% of the administered radioactivity following an iv dose of [14C]PA (90 mg/kg) was excreted in the bile in 60 min; no unchanged PA was detected in the bile. The excretion of radioactivity in the bile was decreased in diethyl maleate-pretreated mice. Only a small amount of the administered radioactivity was recovered in the feces and as expired CO2. The unchanged PA concentration-time curve in plasma was best fit by three, two, and one compartment open models after iv, ip, and po administration, respectively. Based on these results, it was concluded that metabolism and not excretion of unchanged parent penicillic acid is the major process of elimination of PA from the blood. There are extensive route-dependent differences in the kinetic behavior of PA.

The absorption, distribution, and excretion of 14C-penicillic acid by rats.

Adult male and female rats were given 14C-penicillic acid (labeled in the 1, 3, and 5 positions by fermentation with acetate-1-14C) by oral intubation and were sacrificed at 1, 2, 4, 24, 48, 72, and 168 hours following administration of the labeled compound. Approximately 98 p. 100 of the 14C-radioactivity given was absorbed from the gastrointestinal tract of the rats during the first 48 hours. After 7 days, 82 p. 100 was recovered in the urine and 13 p. 100 in the feces. Less than 1 p. 100 of the total radioactivity was recovered as 14CO2 from the expired air; most of this amount was recovered within the first 72 hours after administration. Various tissues were, analyzed for 14C-radioactivity throughout the 7-day-period; no significant retention of radioactivity was apparent in any of the tissues examined. The level of 14C-penicillic acid reached a maximum in the blood and tissues 2-4 hours after administration. Red blood cells contained the highest concentration of 14C-radioactivity. Liver, bladder, kidneys, heart, and bile also showed a high level of 14C-radioactivity concentration. The estimated biological half-life of penicillic acid was 18.7 and 17.1 hours for the male and female, respectively. The estimated biological half-retention time from the point of administration by the red blood cells, liver, and kidney of the male and female rats was 24.2 and 14.0; 19.8 and 17.8; and 21.3 and 19.0 hours, respectively. Recovery studies indicated no unchanged penicillic acid in the urine.