Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumorigenesis by 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone, an in vivo beta-glucuronidase inhibitor.
2,5-Di-O-acetyl-D-glucaro-1,4:6,3-dilactone ( DAGDL ) is a slow release form of D-glucaro-1,4-lactone (GL), a non-toxic natural inhibitor of beta-glucuronidase. When administered orally to female rats in conjunction with a carcinogenic dose of 7,12-dimethylbenzanthracene (DMBA), this compound caused a 70% reduction in the number of rats with mammary tumors and 72% reduction in the number of mammary tumors per rat. Co-administration also reduces the induction by DMBA of a 60 kd oncofetal protein, previously shown to be associated with carcinogenesis and tumorigenesis. DAGDL administration depressed beta-glucuronidase activity both in the absence and presence of concurrent treatment with DMBA and also markedly reduced binding of DMBA to organ DNA. The anti-carcinogenic effect of DAGDL appears to be independent of route of administration of DMBA. It is proposed that inhibition of beta-glucuronidase increases the proportion of DMBA which is sequestered and excreted as the glucuronide and therefore unavailable for activation to the proximal carcinogen.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D001798:Blood Proteins / Q000032:analysis; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002474:Cell-Free System; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005937:Glucaric Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013400:Sugar Acids / Q000494:pharmacology*; D014018:Tissue Distribution
C032223:7,12-dimethylbenzanthracene-binding protein, rat; D001551:Benz(a)Anthracenes; D001798:Blood Proteins; D002352:Carrier Proteins; D013400:Sugar Acids; C038936:aceglatone; D015127:9,10-Dimethyl-1,2-benzanthracene; D012313:RNA; D005966:Glucuronidase; D005937:Glucaric Acid