32P-post-labelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole and other naturally-occurring alkenylbenzenes. I. Adult female CD-1 mice.
The binding of a series of alkenylbenzenes to liver DNA of adult female CD-1 mice, isolated 24 h after i.p. administration of non-radioactive test compound (2 or 10 mg/mouse), was investigated by a modified 32P-post-labelling assay. The known hepatocarcinogens, safrole, estragole and methyleugenol, exhibited the strongest binding to mouse-liver DNA (1 adduct in 10 000 - 15 000 DNA nucleotides or 200 - 300 pmol adduct/mg DNA after administration of a 10 mg dose), while several related compounds, which have not been shown thus far to be carcinogenic in rodent bioassays, bound to mouse-liver DNA at 3 - 200x lower levels. The latter compounds included allylbenzene, anethole, myristicin, parsley apiol, dill apiol and elemicin. Eugenol did not bind. Low binding to mouse-liver DNA was also observed for the weak hepatocarcinogen, isosafrole. Two main 32P-labelled adducts, which appeared to be guanine derivatives, were detected for each of the binding chemicals on thin-layer chromatograms. The loss of safrole adducts from liver DNA was biphasic: a rapid loss during the first week (t 1/2 approximately 3 days) was followed by a much slower decline up to 20 weeks after treatment (t 1/2 approximately 2.5 months). Adducts formed by reaction of 1'-acetoxysafrole, a model ultimate carcinogen, with mouse-liver DNA in vitro were chromatographically identical to safrole-DNA adducts formed in vivo. Pretreatment with pentachlorophenol, a known inhibitor of sulphotransferases, inhibited the binding of safrole to mouse-liver DNA, providing further evidence that the metabolic activation of the allylbenzenes proceeds by the formation of 1'-hydroxy derivatives as proximate carcinogens and 1'-sulphoöxy derivatives as ultimate carcinogens.
D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000378:metabolism*; D001555:Benzene Derivatives / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004149:Dioxoles / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010416:Pentachlorophenol / Q000494:pharmacology; D010761:Phosphorus Radioisotopes; D012451:Safrole / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000081248:Allylbenzene Derivatives; D000840:Anisoles; D001555:Benzene Derivatives; D002273:Carcinogens; D004149:Dioxoles; D010761:Phosphorus Radioisotopes; D004247:DNA; C007633:estragole; D010416:Pentachlorophenol; D012451:Safrole