Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n-pentylnitrosamine depentylation by rat esophageal microsomes, human and rat CYP2E1, and Rat CYP2A3.
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 microM MPN by rat CYP2E1 was 5-12 microM for diallyl sulfide (DAS), diallyl disulfide (DADS), and PEITC and 10-20 microM 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 microM for inhibition by DAS and 1.7-70 microM for inhibition by DADS. With PEITC, Ki for MPN depentylation by REM, rat CYP2E1, and rat CYP2A3 was 0.4-4.6 microM. These low Ki and IC50 values may help explain how garlic and Cruciferae inhibit carcinogenesis.
Morris
Chantey R
CR
Eppley Institute for Research in Cancer, Omaha, Nebraska 68198, USA.
Chen
Sheng C
SC
Zhou
Lin
L
Schopfer
Lawrence M
LM
Ding
Xinxin
X
Mirvish
Sidney S
SS
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019607:Brassicaceae / Q000737:chemistry; D065637:Cytochrome P-450 CYP2A6; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D005737:Garlic / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D017879:Isothiocyanates / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D009602:Nitrosamines; D013440:Sulfides; C038491:allyl sulfide; C058305:phenethyl isothiocyanate; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C585519:Cyp2a3 protein, rat; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6