Failure of catalase to protect against aflatoxin B1-induced mouse lung tumorigenicity.
The carcinogenic mycotoxin aflatoxin B(1) (AFB(1)) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G-->T transversion mutation in K-ras, an early event in AFB(1)-induced mouse lung carcinogenesis, is thought to result from AFB(1)-8,9-exo-epoxide binding to DNA to form AFB(1)-N(7)-guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB(1) carcinogenicity. The objective of this study was to determine whether PEG-CAT would prevent AFB(1) tumorigenicity. Mouse lung tumorigenesis was assessed following treatment of female A/J mice with 300 kU/kg PEG-CAT ip and/or 50 mg/kg AFB(1). Mice were killed 7 months post-treatment and tumors greater than 1 mm in diameter were excised. Unexpectedly, the mean number of tumors per mouse in the PEG-CAT+AFB(1) group (8.81+/-3.64, n=47) was greater than that of the group treated with AFB(1) alone (7.05+/-3.45, n=42) (P<0.05). The tumors obtained from mice treated with PEG-CAT+AFB(1) were larger than those from mice treated with AFB(1) alone (P<0.05). There was no difference in K-ras exon 1 mutation spectrum or in the histological diagnosis of tumors between AFB(1) and PEG-CAT+AFB(1) groups (P>0.05). In vitro incubation with mouse liver catalase (CAT) resulted in conversion of [(3)H]AFB(1) into a DNA-binding species, a possible explanation for the results observed in vivo. These results demonstrate that PEG-CAT is not protective against AFB(1) carcinogenicity in mouse lung despite preventing DNA oxidation.
D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D002374:Catalase / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D003627:Data Interpretation, Statistical; D005079:Excipients; D005260:Female; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009154:Mutation / Q000187:drug effects; D011092:Polyethylene Glycols; D018807:Polymorphism, Single-Stranded Conformational; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D004273:DNA, Neoplasm; D005079:Excipients; D011092:Polyethylene Glycols; D016604:Aflatoxin B1; D002374:Catalase