Inhibition by phenylethyl and phenylhexyl isothiocyanate of metabolism of and DNA methylation by N-nitrosomethylamylamine in rats

Qin Huang, Terence A.lawson, Fung Lung Chung, Chantey R.morris, Sidney S.mervish

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Abstract

We investigated the effect of 2-phenylethyl and 6-phenylhexyl isothiocyanate (PEITC and PHITC) on the metabolism of the rat esophageal carcinogen, N-nitrosomethylamylamine (NMAA). PEITC was administered orally to MRC-Wistar rats as single doses of 0.1 or 1.0 mmol/kg, or by other regimens. When esophagi and liver slices from the treated rats were incubated with 23 μM NMAA, the formation of 2-to 5-hydroxy-NMAA was inhibited by 45-90% for esophagus and by 14-19% for liver slices. In contrast, when esophagi and liver slices from untreated MRC-Wistar rats were incubated in vitro with NMAA and 10 μM PEITC, the PEITC inhibited hydroxy-NMAA formation similarly (by 79-89%) in the two tissues. Also, PEITC inhibited the formation from NMAA of the hydroxy-NMAAs, formaldehyde and pentaldehyde by esophageal and liver microsomes to similar extents. In studies on DNA methylation by NMAA, 7- and O6-methylguanine (O6-MeG) were determined by HPLC with fluorimetric detection. Guanine methylation in esophageal and liver DNA was generally close to linear for doses of 5-50 mg NMAA/kg. With 50 mg NMAA/kg, guanine methylation in esophageal and liver DNA peaked after 5 h, and 8-11% of the peak O6-MeG persisted after 72 h. A single dose of 0.1 or 1.0 mmol PEITC/kg reduced the O6-MeG levels by 44-51% in the esophagus but by only 7-22% in the liver. Administration of the PEITC homolog, PHITC, inhibited NMAA metabolism by liver slices from the treated rats and the methylation of guanine in liver DNA, but had little effect in the esophagus, i.e. PHITC tended to have the opposite tissue specificity to PEITC. The finding that administration of PEITC specifically inhibited NMAA metabolism in the rat esophagus supports the view that PEITC may be a useful chemopreventive agent against esophageal carcinogenesis in humans.

Original languageEnglish (US)
Pages (from-to)749-754
Number of pages6
JournalCarcinogenesis
Volume14
Issue number4
DOIs
StatePublished - Apr 1 1993

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N-amyl-N-methylnitrosamine
DNA Methylation
Esophagus
Liver
Guanine
Methylation
Wistar Rats
DNA
phenethyl isothiocyanate

ASJC Scopus subject areas

  • Cancer Research

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Inhibition by phenylethyl and phenylhexyl isothiocyanate of metabolism of and DNA methylation by N-nitrosomethylamylamine in rats. / Huang, Qin; A.lawson, Terence; Chung, Fung Lung; R.morris, Chantey; S.mervish, Sidney.

In: Carcinogenesis, Vol. 14, No. 4, 01.04.1993, p. 749-754.

Research output: Contribution to journalArticle

Huang, Qin ; A.lawson, Terence ; Chung, Fung Lung ; R.morris, Chantey ; S.mervish, Sidney. / Inhibition by phenylethyl and phenylhexyl isothiocyanate of metabolism of and DNA methylation by N-nitrosomethylamylamine in rats. In: Carcinogenesis. 1993 ; Vol. 14, No. 4. pp. 749-754.
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abstract = "We investigated the effect of 2-phenylethyl and 6-phenylhexyl isothiocyanate (PEITC and PHITC) on the metabolism of the rat esophageal carcinogen, N-nitrosomethylamylamine (NMAA). PEITC was administered orally to MRC-Wistar rats as single doses of 0.1 or 1.0 mmol/kg, or by other regimens. When esophagi and liver slices from the treated rats were incubated with 23 μM NMAA, the formation of 2-to 5-hydroxy-NMAA was inhibited by 45-90{\%} for esophagus and by 14-19{\%} for liver slices. In contrast, when esophagi and liver slices from untreated MRC-Wistar rats were incubated in vitro with NMAA and 10 μM PEITC, the PEITC inhibited hydroxy-NMAA formation similarly (by 79-89{\%}) in the two tissues. Also, PEITC inhibited the formation from NMAA of the hydroxy-NMAAs, formaldehyde and pentaldehyde by esophageal and liver microsomes to similar extents. In studies on DNA methylation by NMAA, 7- and O6-methylguanine (O6-MeG) were determined by HPLC with fluorimetric detection. Guanine methylation in esophageal and liver DNA was generally close to linear for doses of 5-50 mg NMAA/kg. With 50 mg NMAA/kg, guanine methylation in esophageal and liver DNA peaked after 5 h, and 8-11{\%} of the peak O6-MeG persisted after 72 h. A single dose of 0.1 or 1.0 mmol PEITC/kg reduced the O6-MeG levels by 44-51{\%} in the esophagus but by only 7-22{\%} in the liver. Administration of the PEITC homolog, PHITC, inhibited NMAA metabolism by liver slices from the treated rats and the methylation of guanine in liver DNA, but had little effect in the esophagus, i.e. PHITC tended to have the opposite tissue specificity to PEITC. The finding that administration of PEITC specifically inhibited NMAA metabolism in the rat esophagus supports the view that PEITC may be a useful chemopreventive agent against esophageal carcinogenesis in humans.",
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T1 - Inhibition by phenylethyl and phenylhexyl isothiocyanate of metabolism of and DNA methylation by N-nitrosomethylamylamine in rats

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N2 - We investigated the effect of 2-phenylethyl and 6-phenylhexyl isothiocyanate (PEITC and PHITC) on the metabolism of the rat esophageal carcinogen, N-nitrosomethylamylamine (NMAA). PEITC was administered orally to MRC-Wistar rats as single doses of 0.1 or 1.0 mmol/kg, or by other regimens. When esophagi and liver slices from the treated rats were incubated with 23 μM NMAA, the formation of 2-to 5-hydroxy-NMAA was inhibited by 45-90% for esophagus and by 14-19% for liver slices. In contrast, when esophagi and liver slices from untreated MRC-Wistar rats were incubated in vitro with NMAA and 10 μM PEITC, the PEITC inhibited hydroxy-NMAA formation similarly (by 79-89%) in the two tissues. Also, PEITC inhibited the formation from NMAA of the hydroxy-NMAAs, formaldehyde and pentaldehyde by esophageal and liver microsomes to similar extents. In studies on DNA methylation by NMAA, 7- and O6-methylguanine (O6-MeG) were determined by HPLC with fluorimetric detection. Guanine methylation in esophageal and liver DNA was generally close to linear for doses of 5-50 mg NMAA/kg. With 50 mg NMAA/kg, guanine methylation in esophageal and liver DNA peaked after 5 h, and 8-11% of the peak O6-MeG persisted after 72 h. A single dose of 0.1 or 1.0 mmol PEITC/kg reduced the O6-MeG levels by 44-51% in the esophagus but by only 7-22% in the liver. Administration of the PEITC homolog, PHITC, inhibited NMAA metabolism by liver slices from the treated rats and the methylation of guanine in liver DNA, but had little effect in the esophagus, i.e. PHITC tended to have the opposite tissue specificity to PEITC. The finding that administration of PEITC specifically inhibited NMAA metabolism in the rat esophagus supports the view that PEITC may be a useful chemopreventive agent against esophageal carcinogenesis in humans.

AB - We investigated the effect of 2-phenylethyl and 6-phenylhexyl isothiocyanate (PEITC and PHITC) on the metabolism of the rat esophageal carcinogen, N-nitrosomethylamylamine (NMAA). PEITC was administered orally to MRC-Wistar rats as single doses of 0.1 or 1.0 mmol/kg, or by other regimens. When esophagi and liver slices from the treated rats were incubated with 23 μM NMAA, the formation of 2-to 5-hydroxy-NMAA was inhibited by 45-90% for esophagus and by 14-19% for liver slices. In contrast, when esophagi and liver slices from untreated MRC-Wistar rats were incubated in vitro with NMAA and 10 μM PEITC, the PEITC inhibited hydroxy-NMAA formation similarly (by 79-89%) in the two tissues. Also, PEITC inhibited the formation from NMAA of the hydroxy-NMAAs, formaldehyde and pentaldehyde by esophageal and liver microsomes to similar extents. In studies on DNA methylation by NMAA, 7- and O6-methylguanine (O6-MeG) were determined by HPLC with fluorimetric detection. Guanine methylation in esophageal and liver DNA was generally close to linear for doses of 5-50 mg NMAA/kg. With 50 mg NMAA/kg, guanine methylation in esophageal and liver DNA peaked after 5 h, and 8-11% of the peak O6-MeG persisted after 72 h. A single dose of 0.1 or 1.0 mmol PEITC/kg reduced the O6-MeG levels by 44-51% in the esophagus but by only 7-22% in the liver. Administration of the PEITC homolog, PHITC, inhibited NMAA metabolism by liver slices from the treated rats and the methylation of guanine in liver DNA, but had little effect in the esophagus, i.e. PHITC tended to have the opposite tissue specificity to PEITC. The finding that administration of PEITC specifically inhibited NMAA metabolism in the rat esophagus supports the view that PEITC may be a useful chemopreventive agent against esophageal carcinogenesis in humans.

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