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.

Effects of the mycotoxins citrinin and ochratoxin a on hepatic mixed-function oxidase and adenosinetriphosphatase in neonatal rats.

The effects of citrinin, ochratoxin A, or a combination of the two mycotoxins on the hepatic monooxygenase system and on hepatic and renal adenosinetriphosphatase (ATPase) activities were examined in neonatal rats exposed to a single treatment of one or both toxins. Animals received (po) 25 mg/kg citrinin, 1 mg/kg ochratoxin A, or 25 mg/kg citrinin plus 1 mg/kg ochratoxin A within 24 h of birth. Pups were killed 12 d later. Citrinin or ochratoxin A alone did not affect hepatic ATPase. Renal oligomycin-sensitive Mg2+-ATPase was inhibited to the same degree by ochratoxin A and the combination treatment. A synergistic effect of the two mycotoxins was observed on renal Na+-K+-ATPase. Significant effects, due to the mycotoxin interaction, were also observed on cytochrome P-450 content, NADPH-dependent dehydrogenase, and NADPH-cytochrome c reductase.

Effect of patulin on hepatic monooxygenase in male mice.

The in vivo effects of patulin on hepatic monooxygenase enzymes in male mice were examined after single and multiple exposures (i.p.) to the mycotoxin. The animals were exposed to a single dose of 1, 3 or 4.5 mg patulin/kg or daily doses of 1.0 mg/kg for 5 or 14 days. After single exposure no significant effect was observed on hexobarbital hydroxylation while aniline hydroxylase increased significantly at 3 mg/kg and at 48 hr. The demethylation of aminopyrine and ethylmorphine increased significantly 48 and 72 hr after 3.0 or 4.5 mg patulin/kg doses. A 12% increase was observed in cytochrome P-450 content 48 hr after exposure to 1 or 3 mg/kg. NADPH-cytochrome C reductase was enhanced significantly at all 3 dose levels at 48 hr. At 24 hr hepatic NADPH-dependent dehydrogenase activity increased 38 and 46% in animals exposed to a single dose of 3 mg patulin/kg, respectively. No effect of patulin was observed on the hepatic drug metabolizing enzymes examined except hexobarbital oxidation in mice exposed to multiple doses of patulin. Patulin at best was a weak inducer of the hepatic mixed function oxidase system.

Effects of rubratoxin B on the hepatic monooxygenase system in phenobarbital and 3-methylcholanthrene induced male mice.

Alterations in the hepatic microsomal monooxygenase system and in the concentrations of rubratoxin B in urine and feces were examined in male mice pretreated with corn oil, phenobarbital or 3-methylcholanthrene (3MC) and then given a single i.p. dose of rubratoxin B (1 mg/2.5 ml propylene glycol/kg). Twenty-four hours later the following parameters were determined; hepatic cytochrome P-450 content, enzyme activities of NADPH-cytochrome c reductase, NADPH-dependent dehydrogenase, aniline hydroxylase and ethylmorphine N-demethylase, and hepatic microsomal protein and reduced glutathione levels. Excretion of rubratoxin B in urine and feces also was determined. Rubratoxin B reduced the elevated cytochrome P-450 (136%, 134%) and protein (128%, 112%) to control values in animals pretreated with phenobarbital or 3MC, respectively; whereas, in the corn oil pretreated group, the mycotoxin reduced cytochrome P-450 by 38%. Aniline hydroxylase activity was reduced 31% or more in all pretreated animals. Rubratoxin B did not affect ethylmorphine N-demethylase activity in mice pretreated with phenobarbital; however, the enzyme activity was decreased significantly in the 3MC group. Rubratoxin B reduced the hepatic glutathione level in animals receiving 3MC (33%) or corn oil (22%). More rubratoxin B was detected in the urine than in the feces regardless of animals from the 3MC group. These data suggest a greater effect of rubratoxin B in the 3MC pretreated mice than in the phenobarbital pretreated animals.

Aflatoxin B1; its role in the etiology of Reye's syndrome.

Seven cases of Reye's syndrome in which aflatoxin B1 was isolated from the blood or liver or both are presented. In two cases aflatoxin B1 was found in the blood during the acute phase of the disease; a finding not previously reported. In six cases aflatoxin B1 was recovered from autopsy specimens of liver. A number of case reports linking aflatoxin B1 to Reye's syndrome have appeared in the literature but until now only one case had been reported from the United States. Aflatoxin B1 and its possible role in the etiology of Reye's syndrome is discussed. It is concluded that Reye's syndrome is the result of multiple interrelated factors.