Vol. 9, No 1, 2002 pp. 57 - 63
UC 616.61-002.828
MESNA PROTECTS RATS AGAINST NEPHROTOXICITY
BUT NOT CARCINOGENICITY INDUCED BY OCHRATOXIN
A, IMPLICATING TWO SEPARATE PATHWAYS
A. Pfohl-Leszkowicz1, H. Bartsch2,
B.Azémar1, U. Mohr3,
J. Esteve4, M. Castegnaro1,4,5
1Ecole Nationale Supérieure Agronomique,
Laboratoire de Toxicologie et Sécurité Alimentaire,
l Avenue de l'Agrobiopôle, 31326 Auzeville-Tolosane, France
2German Cancer Research Centre, Division
of Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280,
69120, Heidelberg Germany
3Institute for Experimental Pathology,
30625 Hannover Germany
4International Agency for Research
on Cancer, 150 Cours A. Thomas, 69372 Lyon Cedex 08, France
5Consultant, les Collanges, 07240 Saint
Jean Chambre, France
E-mail: castegnaro.marcel@free.fr
; leszkowicz@ensat.fr
Summary. Ochratoxin A (OTA) a nephrotoxic mycotoxin, probably implicated
in human Balkan Endemic Nephropathy, induces renal carcinomas in rats,
the males being more affected than the females. OTA induces DNA adduct
formation, but the structure of these adducts and their role in nephrotoxicity,
genotoxicity and carcinogenicity has only partly been elucidated. Earlier
studies suggested that lipid peroxidation (LPO) is involved in the carcinogenic
and genotoxic effects of OTA and that enzymes implicated in arachidonic
acid metabolism participate in the biotransformation of OTA. Since 2-mercaptoethane
sulfonate (MESNA) protect rats against nephrotoxicity and carcinogenicity
induced by oxidative stress by increasing free thiol groups in kidney,
the potential protective effect of MESNA on renal toxicity and carcinogenicity
induced by OTA was examined of in a long term rat study. MESNA decreased
significantly OTA-induced karyomegalies (p=0.018) in the kidney of male
Dark Agouty and Lewis rats and also the number of individual DNA adduct,
but did not protect against renal adenocarcinomas in male Dark Agouty,
even the incidence is increased. Some kidney OTA-DNA adducts persisted.
Therefore other agents involved in glutathion peroxidase activity have
been tested in an acute study. Pretreatment of male rats by N-acetylcysteine
(NAC), (another agent which, like MESNA, reduces oxidative stress by increase
of free thiol in kidney), buthionine sulfoximine (BSO) (an inhibitor of
glutathionesyntase) and acivicin (an inhibitor of gamma glutamyl transpeptidase
(GGT)) modified the repartition of individual spots as detected by 32P-postlabelling.
Altogether these results demontrate i) separate mechanisms for the induction
of karyomegalies and tumours by OTA in rat kidneys, ii) that OTA induced
OTA-bound DNA adducts in addition of putative LPO-derived exocyclic DNA
adducts iii) implication of glutathion pathway in the formation of DNA-reactive
OTA metabolites and iv) allow to pinpoint that a quinone pathway is probably
involved in renal genotoxicity and carcinogenicity by OTA.
Key words: Ochratoxin A, carcinogenesis, nephrotoxicity, DNA
adducts, 2-mercaptoethane sulfonate (MESNA), oxidative pathway, glutathione
