Modulation of N-nitrosomethylbenzylamine bioactivation by diallyl sulfide in vivo

Abstract

Diallyl sulfide (DAS*), a major flavour and fragrance component of garlic oil (1), has been shown to be an effective inhibitor of tumorigenesis by diverse metabolically activated chemical carcinogens <2-5). In the most striking example of chemoprevention, Wargovich and co-workers reported (4) that pretreatment with DAS completely prevented the formation in rat oesophagus of both malignant and premalignant lesions by /V-nitrosomethylbenzylamine (NMBzA), an exceptionally potent and selective oesophageal carcinogen in this species (6). After preadministration of DAS, a significant reduction has been observed in nuclear aberrations induced by NMBzA and dimethylhydrazine (4,7) but not in the nucleotoxicity of the direct-acting methylating•Abbreviations: DAS, diallyl sulfide; NMBzA, N-nitrosomethylbenzylamine; O^-MEdG, C^-methyldeoxyguanosine, 7-MEdG, 7-methyldeoxyguanosine.© Oxford University Press carcinogens /V-nitrosomethylurea and /V-methyl-/V'-nitro-/Vnitrosoguanidine (7). Studies in vitro have shown that DAS also is an inhibitor of oxidative metabolism by cytochrome P450 enzymes of a number of carcinogenic nitrosamines, including NMBzA, /V-nitrosodimethylamine, /V-nitrosodiethylamine and 4-(A'-memyl-A^-nirjosarnino)-l-(3-pyridyl)-l-butanone (4,(8)(9)(10). These findings suggested that DAS may block nitrosamineinduced tumorigenesis by inhibiting nitrosamine bioactivation in situ. In the present investigation, we have examined this possibility by assessing the effects of DAS on the overall metabolism of NMBzA and on DNA methylation by NMBzA in vivo.In the protocol developed by Wargovich and co-workers (4), rats received five weekly treatments consisting of an i.g. dose of 200 mg/kg of DAS followed 3 h later by a s.c. injection of 3.5 mg/kg of NMBzA. However, in vitro demethylation of NMBzA was significantly lower by hepatic microsomes prepared 18 h after a similar dose of DAS than by microsomes collected 3 h post-treatment (8). In order to determine whether there is a similar difference in vivo between immediate and delayed effects of DAS on overall NMBzA metabolism, we monitored the formation of 14 CO 2 and radioactive urinary metabolites from [methyll4

Modulation of phase I and phase II xenobiotic‐metabolizing enzymes by selenium‐enriched garlic in rats

“…Garlic sulfides have been reported to modulate P-450 isozymes (18)(19)(20)(21), block carcinogen activation (22)(23)(24)(25), diminish carcinogen-induced nuclear damage (22,26), and stimulate glutathione S-transferase (26)(27)(28)(29). Milner and coworkers (30,31) also showed that natural garlic and its constituents are able to inhibit the formation of DMBA-DNA adducts in rat mammary cells.…”

Garlic and Onions: Their Cancer Prevention Properties

“…Aqueous garlic extracts reduced the mutagenicity of ionizing radiation, peroxides, Adriamycin, and N-methyl-N′-nitrosoguanidine (61). DAS diminished the DNA hypermethylation of esophagus, liver, and nasal mucosa that arose from treatment with N-nitrosomethylbenzylamine (62). However, Cohen et.…”

Garlic and its Organosulfides as Potential Chemopreventive Agents: A Review

“…DNA methylation and histone acetylation can be modified by enhanced intake of garlic and/or related allyl sulfur compounds. In another study Leudeke et al [103] reported that DAS inhibited the formation of O 6 -methyldeoxy guanosine in esophagus (26%), nasal mucosa (51%), trachea (68%) and lung (78%) induced by N-nitrosomethyl benzylamine. Similarly, Lin et al [94] and Schaffer et al [104] provide evidences that DAD, SAC and deodorized garlic are effective in retarding the DNA methylation caused by N-methyl-N-nitrosourea.…”