TY - JOUR
T1 - Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n-pentylnitrosamine depentylation by rat esophageal microsomes, human and rat CYP2E1, and rat CYP2A3
AU - Morris, Chantey R.
AU - Chen, Sheng C.
AU - Zhou, Lin
AU - Schopfer, Lawrence M.
AU - Ding, Xinxin
AU - Mirvish, Sidney S.
N1 - Funding Information:
This research was supported by grant RO1-CA-35628 and core grant P30-CA-36727 from the National Cancer Institute, grant RO1-ES-07462 from the National Institute for Environmental Health Sciences, grant 97B-125 from the American Institute of Cancer Research, and the Environmental Toxicology Fellowship Program of the University of Nebraska for a fellowship to C. R. Morris. Address correspondence to S. S. Mirvish, Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42nd & Dewey Avenues, 986805 Nebraska Medical Center, Omaha, NE 68198. E-mail: smirvish@unmc.edu.
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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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U2 - 10.1207/s15327914nc4801_8
DO - 10.1207/s15327914nc4801_8
M3 - Article
C2 - 15203378
AN - SCOPUS:3042692972
VL - 48
SP - 54
EP - 63
JO - Nutrition and Cancer
JF - Nutrition and Cancer
SN - 0163-5581
IS - 1
ER -