title: Inhibition of methyl-n-amylnitrosamine hydroxylation by diallyl sulfide and phenethylisothiocyanate in the rat.
abstract: Formation of the stable 2-, 3-, and 4-hydroxy derivatives of methyl-n-amylnitrosamine (MNAN) probably reflects cytochrome P-450-catalyzed activation of MNAN by 1-hydroxylation. Here we studied inhibition of the oxidation of MNAN to hydroxy-MNANs (HO-MNANs) by freshly excised tissues from MRC-Wistar rats treated with the vegetable-derived chemicals diallyl sulfide (DAS) and phenethylisothiocyanate (PEITC). Rats were gavaged with DAS (200 mg/kg), PEITC (163 mg/kg), or vehicle (corn oil) alone. After various times, the rats were killed, the esophagus, nasal mucosa, and liver were removed, and the tissues/tissue slices were incubated for two hours with 23 microM MNAN. HO-MNAN formation was measured by gas chromatography-thermal energy analysis. Significant (p < 0.01) 72-75%, 40%, and 44% inhibitions of total HO-MNAN formation were observed for nasal mucosa removed at 3-18 hours, for esophagus at 18 hours, and for liver at 3 hours, respectively, after gavage of DAS. Significant (p < 0.03) 46-75% inhibition of HO-MNAN formations was observed for the esophagus at 2-24 hours after gavage of PEITC. In disposition studies, rats were treated with DAS (200 mg/kg) in corn oil and sacrificed after various intervals. DAS was determined by gas chromatography of tissue homogenate extracts. After gavage of DAS, its total recovery from all tissues studied was 27% of the dose after 45 minutes and 15-19% after 90 and 180 minutes, with > 80% of the recovered DAS in the stomach contents. Up to 2% per tissue of the recovered DAS was found in the stomach wall, liver, and blood. After intraperitoneal injection of DAS, < or = 2% of the dose was recovered in the blood and < or = 0.7% in the liver. Hence, gavage of DAS and PEITC significantly inhibited HO-MNAN formation for up to 18 and 24 hours, respectively, whereas DAS was > 80% metabolized 90 minutes after its gavage. These findings suggest that long-lasting inhibitors or their metabolites, or inactivation of P-450 enzymes, were responsible for the persistence of inhibition of MNAN metabolism.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Morris
authors.forename: S C
authors.initials: SC
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Hinman
authors.forename: S S
authors.initials: SS
authors.lastname: Mirvish
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000378:metabolism*; D002849:Chromatography, Gas; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004947:Esophagus / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D017879:Isothiocyanates / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D009602:Nitrosamines; D013440:Sulfides; C025033:N-amyl-N-methylnitrosamine; C038491:allyl sulfide; C058305:phenethyl isothiocyanate