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Malaria infection modulates effects of genotoxic chemicals in the mouse bone-marrow micronucleus test.

Abstract
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.
AuthorsKátia S Poça, Ana C A X De-Oliveira, Manoel J S Santos, Francisco J R Paumgartten
JournalMutation research (Mutat Res) Vol. 649 Issue 1-2 Pg. 28-33 (Jan 08 2008) ISSN: 0027-5107 [Print] Netherlands
PMID17851116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carcinogens
  • 9,10-Dimethyl-1,2-benzanthracene
  • Cyclophosphamide
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP2B1
Topics
  • 9,10-Dimethyl-1,2-benzanthracene (toxicity)
  • Animals
  • Bone Marrow (drug effects, metabolism)
  • Carcinogens (toxicity)
  • Cyclophosphamide (toxicity)
  • Cytochrome P-450 CYP1A1 (metabolism)
  • Cytochrome P-450 CYP2B1 (metabolism)
  • Female
  • Malaria (blood, parasitology, physiopathology)
  • Mice
  • Mice, Inbred C57BL
  • Micronucleus Tests (methods)
  • Microsomes, Liver (drug effects, enzymology)
  • Plasmodium berghei

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