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Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J mice
K I Eklind1, M A Morse, F L Chung
1Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, NY 10595.
Abstract:
The distribution and metabolism of phenethyl isothiocyanate (PEITC), a naturally occurring anticarcinogen, was investigated in A/J mice. Mice were administered 5 mumol of [14C]PEITC (2 microCi/mouse) by gavage and killed at 1, 2, 4, 8, 24, 48 or 72 h after dosing. Radioactivity present in the spleen, heart, liver, lung, kidney, brain, urine and feces was measured. Lung, the target tissue of PEITC inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) lung tumorigenesis, showed maximum radioactivity between 4 and 8 h after dosing, suggesting this time period would be optimal for maximal inhibition by PEITC in A/J mice. Approximately 50% of the total radioactivity was excreted within 24 h after dosing with nearly 80% of radioactivity found in urine and feces at 72 h. Two metabolites were isolated by reverse-phase HPLC from urine of mice treated with PEITC. The identities of these metabolites were determined by comparison with synthetic standards and by NMR and MS. The major metabolite was a cyclic mercaptopyruvic acid conjugate, whereas the minor metabolite was an N-acetylcysteine conjugate. Approximately 25% of the administered dose of PEITC was excreted as the cyclic mercaptopyruvic acid conjugate and 10% as the N-acetylcysteine conjugate. These results suggest that urinary metabolites of PEITC may provide potentially useful dosimeters for this natural anticarcinogen.
Insights
Phenethyl isothiocyanate (PEITC), a natural anticarcinogen, distributes to mouse lungs for optimal tumor inhibition. Its urinary metabolites, including a cyclic mercaptopyruvic acid conjugate, can serve as dosimeters.
Area of Science:
- Pharmacology
- Toxicology
- Natural Products Chemistry
Background:
- Phenethyl isothiocyanate (PEITC) is a naturally occurring compound with demonstrated anticarcinogenic properties.
- Understanding PEITC's distribution and metabolism is crucial for optimizing its chemopreventive potential, particularly against lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
Purpose of the Study:
- To investigate the pharmacokinetic profile of PEITC in A/J mice.
- To identify and quantify the major metabolites of PEITC in vivo.
- To determine the optimal time window for PEITC administration for maximal chemopreventive effects in the lung.
Main Methods:
- A/J mice were administered radiolabeled [14C]PEITC via oral gavage.
- Radioactivity was measured in various tissues (spleen, heart, liver, lung, kidney, brain), urine, and feces at multiple time points (1-72 hours post-dosing).
- Metabolites in urine were isolated using reverse-phase HPLC and identified using NMR and MS, compared against synthetic standards.
Main Results:
- Peak radioactivity in the lung, the target tissue for NNK-induced lung tumorigenesis inhibition, was observed between 4 and 8 hours post-dosing.
- Approximately 50% of the administered radioactivity was excreted within 24 hours, with nearly 80% found in urine and feces by 72 hours.
- Two major urinary metabolites were identified: a cyclic mercaptopyruvic acid conjugate (approx. 25% of dose) and an N-acetylcysteine conjugate (approx. 10% of dose).
Conclusions:
- The distribution pattern of PEITC suggests an optimal window for its anticarcinogenic activity against NNK-induced lung tumors in A/J mice.
- Urinary metabolites of PEITC, particularly the cyclic mercaptopyruvic acid conjugate, show potential as reliable biomarkers for monitoring PEITC exposure.
- Further research into PEITC metabolism can aid in the development of effective chemopreventive strategies using natural compounds.