Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n-pentylnitrosamine depentylation by rat esophageal microsomes, human and rat CYP2E1, and rat CYP2A3

Chantey R. Morris, Sheng C. Chen, Lin Zhou, Lawrence M. Schopfer, Xinxin Ding, Sidney S. Mirvish

Research output: Contribution to journalArticle

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Abstract

Garlic and Cruciferae are associated with reduced risks of several human cancers, and some of their constituents are anticarcinogenic in animals. Here we studied inhibition of in vitro metabolism of the rat esophageal carcinogen methyl-n-pentylnitrosamine (MPN) by garlic-derived allyl sulfides and by Cruciferae-derived phenethyl isothiocyanate (PEITC) and sulforaphane. The test inhibitors were incubated with [3H]-MPN, NADPH-generating system and rat esophageal microsomes (REM) or a cytochrome P450 (CYP). [3H]-MPN activation by depentylation was assayed by HPLC with radiometric determination of [3H]-pentaldehyde 2,4-dinitrophenylhydrazone. IC50 for depentylation of 40 μM MPN by rat CYP2E1 was 5-12 μM for diallyl sulfide (DAS), diallyl disulfide (DADS), and PEITC and 10-20 μM for diallyl sulfone, allyl mercaptan, and diallyl trisulfide. Maximum inhibition required preincubation of rat CYP2E1 with DAS for 15 min and with DADS for 30 min. Using these preincubation times, Ki for MPN depentylation by REM, rat and human CYP2E1, and rat CYP2A3 was 0.6-1.6 μM for inhibition by DAS and 1.7-70 μM for inhibition by DADS. With PEITC, Ki for MPN depentylation by REM, rat CYP2E1, and rat CYP2A3 was 0.4-4.6 μM. These low Ki and IC50 values may help explain how garlic and Cruciferae inhibit carcinogenesis.

Original languageEnglish (US)
Pages (from-to)54-63
Number of pages10
JournalNutrition and cancer
Volume48
Issue number1
DOIs
StatePublished - Jan 1 2004

Fingerprint

methyl isothiocyanate
Cytochrome P-450 CYP2E1
microsomes
Microsomes
sulfides
rats
diallyl sulfides
Brassicaceae
Garlic
isothiocyanates
garlic
Inhibitory Concentration 50
inhibitory concentration 50
allyl sulfide
phenethyl isothiocyanate
allyl isothiocyanate
carcinogens
thiols
NADP
Sulfhydryl Compounds

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Oncology
  • Nutrition and Dietetics
  • Cancer Research

Cite this

Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n-pentylnitrosamine depentylation by rat esophageal microsomes, human and rat CYP2E1, and rat CYP2A3. / Morris, Chantey R.; Chen, Sheng C.; Zhou, Lin; Schopfer, Lawrence M.; Ding, Xinxin; Mirvish, Sidney S.

In: Nutrition and cancer, Vol. 48, No. 1, 01.01.2004, p. 54-63.

Research output: Contribution to journalArticle

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abstract = "Garlic and Cruciferae are associated with reduced risks of several human cancers, and some of their constituents are anticarcinogenic in animals. Here we studied inhibition of in vitro metabolism of the rat esophageal carcinogen methyl-n-pentylnitrosamine (MPN) by garlic-derived allyl sulfides and by Cruciferae-derived phenethyl isothiocyanate (PEITC) and sulforaphane. The test inhibitors were incubated with [3H]-MPN, NADPH-generating system and rat esophageal microsomes (REM) or a cytochrome P450 (CYP). [3H]-MPN activation by depentylation was assayed by HPLC with radiometric determination of [3H]-pentaldehyde 2,4-dinitrophenylhydrazone. IC50 for depentylation of 40 μM MPN by rat CYP2E1 was 5-12 μM for diallyl sulfide (DAS), diallyl disulfide (DADS), and PEITC and 10-20 μM for diallyl sulfone, allyl mercaptan, and diallyl trisulfide. Maximum inhibition required preincubation of rat CYP2E1 with DAS for 15 min and with DADS for 30 min. Using these preincubation times, Ki for MPN depentylation by REM, rat and human CYP2E1, and rat CYP2A3 was 0.6-1.6 μM for inhibition by DAS and 1.7-70 μM for inhibition by DADS. With PEITC, Ki for MPN depentylation by REM, rat CYP2E1, and rat CYP2A3 was 0.4-4.6 μM. These low Ki and IC50 values may help explain how garlic and Cruciferae inhibit carcinogenesis.",
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