Inhibition of sulfotransferase affecting in vivo genotoxicity and DNA adducts induced by safrole in rat liver.
The effect of pretreatment with pentachlorophenol (PCP), a known inhibitor of sulfotransferases, on the induction of chromosomal aberrations, sister chromatid exchanges (SCEs), replicative DNA synthesis (RDS), and the formation of DNA adducts was studied in the liver of rats treated with safrole (1-allyl-3,4-methylenedioxy-benzene). Rats were given a single oral dose (1,000 mg/kg body weight) or 5 repeated doses (500 mg/kg body weight) of safrole, with or without intraperitoneal pretreatment with PCP (10 mg/kg body weight). Hepatocytes were isolated 24 hr after administration of safrole and allowed to proliferate in Williams' medium E supplemented with epidermal growth factor to test for chromosomal aberrations and SCEs. For examination of RDS, hepatocytes were incubated in Williams' medium E containing 5-bromo-2'-deoxyuridine. Safrole-DNA adducts were detected by a nuclease P1-enhanced 32P-postlabeling assay. A single dose of safrole induced significant SCEs and RDS, while chromosomal aberrations were induced by 5 repeated doses. Two major and 2 minor DNA adducts were detected by both a single dose and 5 repeated doses. PCP significantly decreased safrole-induced cytogenetic effects and RDS, and caused a decrease in DNA adducts formed by safrole. These results suggest that safrole is capable of inducing SCEs, chromosomal aberrations, and RDS in the rat liver in vivo and that these effects may be induced by the sulfuric acid ester metabolite that can bind DNA.
Daimon
H
H
Drug Safety Research Laboratories, Eisai Co., Ltd., Gifu-ken, Japan.
Sawada
S
S
Asakura
S
S
Sagami
F
F
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002869:Chromosome Aberrations; D018736:DNA Adducts / Q000032:analysis*; D004261:DNA Replication; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D010416:Pentachlorophenol / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012451:Safrole / Q000633:toxicity*; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*
D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D010416:Pentachlorophenol; D015238:Sulfotransferases; D012451:Safrole