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Interaction of secalonic acid D with phenobarbital, 3-methyl cholanthrene, and SKF-525A in mice
Abstract:
Secalonic acid D (SAD) is an acutely toxic and teratogenic fungal metabolite produced by Penicillium oxalium in corn and other cereal grains. Experiments were conducted to study the effects of single and multiple doses of SAD on pentobarbital-induced narcosis, as an index of the modulating effect of SAD on the hepatic drug metabolizing enzymes in mice. The effects of known enzyme modulators-phenobarbital (PB), 3-methyl cholanthrene (3-MC), and diethylaminoethyl diphenylproply acetate hydrochloride (SKF-525A)-on the acute toxicity of SAD in mice were also studied using body weights, mortality, and histopathology as indices. Results of this study failed to demonstrate any modulating effect by SAD of pentobarbital metabolizing enzymes. Pretreatment with SKF-525A, an enzyme inhibitor, enhanced SAD toxicity in mice, whereas pretreatment with PB or 3-MC, known enzyme inducers, had no effect. Further studies of interaction of [14C]SAD with PB and SKF-525A revealed that although neither PB nor SKF-525A altered the ratio of parent compound to total metabolites excreted in bile, SKF-525A significantly reduced the bile flow as well as the elimination of SAD-derived radioactivity in bile. These results strongly suggest the possibility that the effects of SKF-525A, other than the enzyme inhibition, may be responsible for its enhancement of SAD toxicity in mice.
Insights
Secalonic acid D (SAD), a fungal toxin, did not affect liver enzymes that metabolize drugs. However, an enzyme inhibitor, SKF-525A, increased SAD toxicity, suggesting non-enzyme related mechanisms contribute to its toxicity.
Area of Science:
- Toxicology
- Mycology
- Pharmacology
Background:
- Secalonic acid D (SAD) is a toxic fungal metabolite from Penicillium oxalium found in grains.
- SAD exhibits acute toxicity and teratogenicity.
- Hepatic drug metabolizing enzymes play a role in toxin detoxification.
Purpose of the Study:
- To investigate the effect of SAD on pentobarbital-induced narcosis, an indicator of hepatic drug metabolizing enzyme activity.
- To determine how known enzyme modulators (phenobarbital, 3-methyl cholanthrene, SKF-525A) affect the acute toxicity of SAD in mice.
Main Methods:
- Mice were administered single or multiple doses of SAD to assess effects on pentobarbital-induced narcosis.
- Acute toxicity of SAD was evaluated in mice pretreated with enzyme inducers (phenobarbital, 3-methyl cholanthrene) or an inhibitor (SKF-525A).
- Interactions between [14C]SAD and modulators were studied by analyzing biliary excretion and metabolite ratios.
Main Results:
- SAD did not demonstrate any significant modulating effect on pentobarbital metabolizing enzymes.
- Pretreatment with SKF-525A, an inhibitor, significantly enhanced SAD toxicity.
- Enzyme inducers phenobarbital and 3-methyl cholanthrene did not affect SAD toxicity.
- SKF-525A reduced bile flow and the elimination of SAD radioactivity in bile, independent of altering metabolite ratios.
Conclusions:
- SAD does not appear to modulate hepatic drug metabolizing enzymes involved in pentobarbital metabolism.
- The enhanced toxicity of SAD by SKF-525A may be due to mechanisms other than enzyme inhibition, possibly related to reduced bile flow.
- Further research is needed to elucidate the specific mechanisms underlying SKF-525A's potentiation of SAD toxicity.