Malaria infection modulates effects of genotoxic chemicals in the mouse bone-marrow micronucleus test.
Malaria has been reported to modulate the activity of cytochrome-P450 enzymes (CYP). Since CYPs are involved both in the activation and detoxication of xenobiotics, we investigated whether malaria would modify the effects of chemical carcinogens in the bone-marrow micronucleus assay. Female C57BL6 mice were infected with Plasmodium berghei (ANKA) and treated (ip route) with cyclophosphamide (CPA, 25 mg/kg body weight), 7,12-dimethylbenz[a]anthracene (DMBA, 50mg/kg body weight) or ethyl methanesulfonate (EMS, 150 mg/kg body weight), on post-infection days 9-12 when parasitemia was > or =9% of RBC. Controls were age-paired non-infected mice. Bone marrows were sampled at 24 and 48 h (CPA), 24 h (EMS) or 48 h (DMBA) after treatment. The background incidence of polychromatic erythrocytes with micronuclei (MN-PCE) in malaria-infected mice was approximately twofold the background incidence in non-infected controls. Effects of indirect clastogens (CPA and DMBA) in the micronucleus assay were attenuated while the effect of EMS, a direct clastogen, was enhanced by infection. In a separate experiment, malaria was shown to decrease activities of ethoxy-(EROD, a marker for CYP1A) and benzyloxy-(BROD, CYP2B) resorufin-O-dealkylases in liver microsomes. The foregoing findings are consistent with the hypothesis that malaria-caused attenuation of genotoxicity arose from a down modulation of CYP isoforms that convert CPA (CYP2B) and DMBA (CYP1A) into their active metabolites.
Poça
Kátia S
KS
Laboratory of Environmental Toxicology, Department of Biological Sciences, National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
De-Oliveira
Ana C A X
AC
Santos
Manoel J S
MJ
Paumgartten
Francisco J R
FJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D005260:Female; D008288:Malaria / Q000097:blood / Q000469:parasitology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015162:Micronucleus Tests / Q000379:methods; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010962:Plasmodium berghei
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D003520:Cyclophosphamide; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1