Modulation of N-nitrosomethylbenzylamine bioactivation by diallyl sulfide in vivo.
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.
Ludeke
B I
BI
Department of Pathology, University of Zürich, Switzerland.
Dominé
F
F
Ohgaki
H
H
Kleihues
P
P
D000498:Allyl Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000096:biosynthesis; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004947:Esophagus / Q000737:chemistry / Q000187:drug effects; D005737:Garlic / Q000737:chemistry*; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008745:Methylation; D009831:Olfactory Mucosa / Q000737:chemistry / Q000187:drug effects; D010946:Plants, Medicinal; D051381:Rats; D011916:Rats, Inbred F344; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D000970:Antineoplastic Agents; D002273:Carcinogens; D013440:Sulfides; C038491:allyl sulfide; D004247:DNA; C014707:nitrosobenzylmethylamine; C015558:O(6)-methyl-2'-deoxyguanosine; D003849:Deoxyguanosine; D004128:Dimethylnitrosamine