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Modulation of N-nitrosomethylbenzylamine bioactivation by diallyl sulfide in vivo
B I Ludeke1, F Dominé, H Ohgaki
1Department of Pathology, University of Zürich, Switzerland.
Abstract:
Diallyl sulfide (DAS), a major component of garlic oil, is an inhibitor of tumorigenesis by various metabolically activated carcinogens. In rats, pretreatment with DAS has been observed to suppress completely the induction of oesophageal neoplasms by N-nitrosomethylbenzylamine (NMBzA) (Wargovich et al. (1988) Cancer Res., 48, 6872-6875). This communication reports the effects of DAS on overall NMBzA metabolism and on DNA methylation of NMBzA in vivo under conditions equivalent to a single treatment of the chemoprevention assay. Male Fischer 344 rats received a single i.g. dose of DAS (200 mg/kg body wt) followed by an s.c. injection of [methyl-14C]NMBzA (3.5 mg/kg). In controls, exhalation of 14CO2 was complete within 5 h (t1/2max = 1.2 h), with 50% of the injected radioactivity recovered as 14CO2. When DAS was given 3 h prior to [methyl-14C]NMBzA, 49% of the injected radioactivity was released within 10 h (t1/2max = 3 h). When DAS was administered 18 h before the carcinogen, 42% of [methyl-14C]NMBzA was converted to 14CO2, with exhalation complete after 6 h (t1/2max = 1.8 h). We further examined the effects of acute doses of 10-200 mg/kg of DAS on DNA methylation by a single dose of NMBzA (3.5 mg/kg; survival time, 6 h) administered 3 h later. At 200 mg/kg, DAS inhibited the formation of O6-methyldeoxyguanosine (O6-MEdG) in oesophagus (-26%), nasal mucosa (-51%), trachea (-68%) and lung (-78%). In liver, levels of 7-MEdG were reduced by 43%. Decreases in DNA methylation were proportional to dose for > 25 mg/kg of DAS in oesophagus, liver and nasal mucosa, for 25-200 mg/kg in trachea and 10-50 mg/kg in lung. The dose-activity relationship for inhibition by DAS of DNA methylation by NMBzA suggests that short-term modulation of carcinogen bioactivation in situ contributes to but may not be sufficient for the chemo-prevention of nitrosamine tumorigenesis by DAS.
Insights
Diallyl sulfide (DAS), a garlic oil component, inhibits N-nitrosomethylbenzylamine (NMBzA) metabolism and DNA methylation in rats. This chemopreventive effect suggests modulation of carcinogen bioactivation contributes to tumor prevention.
Area of Science:
- Oncology
- Chemoprevention
- Toxicology
Background:
- Diallyl sulfide (DAS), a key component of garlic oil, is recognized for its potential chemopreventive properties against carcinogens.
- Previous studies indicated DAS can suppress tumorigenesis induced by metabolically activated carcinogens, including N-nitrosomethylbenzylamine (NMBzA).
Purpose of the Study:
- To investigate the effects of Diallyl sulfide (DAS) on the overall metabolism of N-nitrosomethylbenzylamine (NMBzA).
- To determine the impact of DAS on the in vivo DNA methylation by NMBzA under conditions relevant to chemoprevention assays.
Main Methods:
- Male Fischer 344 rats were administered varying doses of DAS followed by [methyl-14C]NMBzA.
- Carcinogen metabolism was assessed by measuring 14CO2 exhalation.
- DNA methylation, specifically O6-methyldeoxyguanosine (O6-MEdG) and 7-MEdG, was quantified in various tissues.
Main Results:
- DAS administration altered NMBzA metabolism, affecting the rate and extent of 14CO2 exhalation.
- Acute doses of DAS significantly inhibited NMBzA-induced DNA methylation in multiple organs, including the esophagus, nasal mucosa, trachea, lung, and liver.
- The inhibition of DNA methylation by DAS was dose-dependent across different tissues.
Conclusions:
- Diallyl sulfide (DAS) effectively modulates N-nitrosomethylbenzylamine (NMBzA) metabolism and significantly reduces its DNA methylation in vivo.
- These findings support the role of short-term modulation of carcinogen bioactivation in the chemopreventive mechanisms of DAS against nitrosamine-induced tumorigenesis.