Abstract
Naturally occurring phenethyl isothiocyanate (PEITC) and its synthetic homolog 6-phenylhexyl isothiocyanate (PHITC) are both effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor development in A/J mice and F344 rats. To help explain why PHITC is considerably more efficacious than PEITC in chemopreventive potency, comparative disposition and pharmacokinetics data for male F344 rats were obtained after a single gavage dose of 50 μmol/kg (3.71 μCi/μmol) [14C]PEITC or 50 μmol/kg (6.59 μCi/μmol) [14C]PHITC in corn oil. After [14C]PEITC dosing, whole blood 14C peaked at 2.9 h, with an elimination half-life (T1/2e) of 21.7 h; blood 14C from [14C]PHITC-treated rats peaked at 8.9 h, with an T1/2e of 20.5 h. In lungs, the target organ, the T1/2e for [14C]PHITC and its labeled metabolites were more than twice that for [14C]PEITC and its labeled metabolites. The effective dose (area under the concentration-time curve) for 14C from PHITC was greater than 2.5 times the area under the concentration-time curve of14C from PEITC in liver, lungs, and several other tissues. During 48 h, approximately 16.5% of the administered dose of [14C]PHITC was expired as [14C]CO2, more than 100 times the [14C]CO2 expired by rats treated with [14C]PEITC. In rats given [14C]PEITC, 88.7 ± 2.2% and 9.9 ± 1.9% of the dose appeared in the urine and feces, respectively, during 48 h; however, rats given [14C]PHITC excreted 7.2 ± 0.8% of the dose of14C in urine and 47.4 ± 14.0% in the feces. Higher effective doses of PHITC in the lungs and other organs may be the basis, in part, for its greater potency as a chemopreventive agent.
Footnotes
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Send reprint requests to: Dr. C. C. Conaway, Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, 1 Dana Road, Valhalla, NY 10595.
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↵1 Present address: Mitsui Norin Co., Ltd., Food Research Laboratories, 233 Miyabara, Fujieda City, Shizouka 426-01, Japan.
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This study was supported by Grant CA46535 from the National Cancer Institute. This article is number 29 in the series “Dietary Inhibitors of Chemical Carcinogenesis”.
- Abbreviations used are::
- PEITC
- phenethyl isothiocyanate
- ITC
- isothiocyanate
- PHITC
- 6-phenylhexyl isothiocyanate
- PEITC-NAC
- N-acetylcysteine conjugate of PEITC
- PHITC-NAC
- N-acetylcysteine conjugate of PHITC
- GSH
- glutathione
- NNK
- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
- AUC
- area under the concentration-time curve
- T1/2a
- half-life of absorption
- T1/2e
- half-life of elimination
- Tmax
- time at maximum concentration
- Cmax
- maximum ITC concentration in tissue
- KCN
- potassium cyanide
- TLC
- thin layer chromatography
- HPLC
- high-pressure liquid chromatography
- The American Society for Pharmacology and Experimental Therapeutics
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