, Il s'agit probablement comme l'a décrit Winterbourn5 °, d'une action directe du radical semiquinone sur les hydroperoxydes organiques préexistants dans les microsomes hépatiques. Ce radical, pourrait en effet, arracher directement un atome d'hydrogène aux hydroperoxydes et

, Nous avons également testé un certain nombre d'antioxydants non enzymatiques

, Dans ce travail, le zinc inhibe nettement la peroxydation microsomale induite par

, Enfin, l'effet inhibiteur du zinc sur la peroxydation microsomale induite par l'adriamycine pourrait également être dû à la stabilisation des membranes lipidiques

, L'effet antioxydant du zinc a déjà été rapporté dans d'autres conditions de stress oxydatif

, En ce sens, le zinc inhibe la peroxydation induite par le CC14 chez l'animal ainsi que dans des préparations de microsomes hépatiques isolésl os. En outre, la peroxydation microsomale induite par l'alcool est plus importante chez les rats déficients en zincl 06. Le zinc inhibe également la production de MDA induite par le système fer-xanthine oxydasexanthine dans les membranes érhythrocytaires

. S'agissa, nt du sélénium, l'incubation préalable des microsomes avec le sélénium ne modifie pas la production des MDA induite par l'adriamycine. En revanche, le sélénium exerce un effet inhibiteur net dans les modèles, vol.5

, Son action est, en effet, liée à l'induction de l'activité glutathion peroxydase.qui ne peut pas s'exercer dans des systèmes isolés

, Nous avons, au cours de ce travail, testé d'autres scavengers des radicaux oxygénés

E. H. Jeffery, The effect of zinc on NADPH oxidation and monooxygenase activity in rat hepatic rrûcrosomes, Mol. Phannacol, vol.23, pp.467-473, 1983.

M. Ryan, J. N. Elias, S. L. Peng, and Y. M. , Protective effect of zinc on carbon tetrachloride-induced liver injury in rats, Exp. Mol. Pharmacol, vol.19, pp.186-196, 1973.

J. F. Jetton, M. M. Hahn, and H. K. , Enhanced lipid peroxiclation in liver microsomes of zinc-deficient rats, Am. J. Clin. Pathol, vol.33, pp.51-56, 1980.

V. T. Devita, Principes de médecine interne, Flammarion Médecine-Sciences éd, pp.1709-1725, 1988.

S. Ci-;-auste-manciet, P. Faure, I. Madelaine, and J. L. Saulnier, Anticancéreux : utilisation pratique. Dossier du CNIMH, hors série, 1992.

P. Poullart, Médicaments cytostatiques-cytolytiques, vol.9, pp.314-330, 1991.

J. Calop, J. Carraz-g-;-calop, and G. Carraz, Pharmacodynamie spéciale, tome 4, Ellipses éd, pp.181-229, 1988.

M. Marty, F. Calvo, M. Espie, J. M. Lagier, I. Florentin et al., Pharmacologie clinique : bases thérapeutiques. Expansion Scientifique Francaise, 2 éd, pp.1894-1945, 1988.

M. Espie, J. M. Extra, and M. Marty, Pharmacologie anticancéreuse, Schorderet M. Pharmacologie, des concepts fondamentaux aux applications thérapeutiques. Frison-Roche 2 éd, pp.795-819, 1992.

M. Clavel, Chimiothérapies anticancéreuses, classification et mode d'action, Rev. Prat, vol.41, issue.26, pp.2759-2766, 1991.

D. Piettre, Classification clinique des anticancéreux à partir de leurs effets indésirables. La Pharmacie hospitalière francaise, vol.94, pp.1379-1396, 1990.

W. C. Rose and J. E. Scuring, Preclinical antitumor and toxicologie profil of carboplatin, Cancer Treat. Rev, vol.12, pp.1-20, 1985.

L. H. Fraisier, S. Kanekal, and . P. Kehrerj, Cyclophosphamide toxicity, charaterising and avoiding the problem, Drugs, vol.42, issue.5, pp.781-795, 1991.

F. M. Mugia and A. C. Louie, Sikic b.I. (1983) Pulmonary toxicity of antitumor agents

, Cancer Treat. Rev, vol.10, pp.221-243

J. Lacroix, T. Jousselin, and R. Lacroix, Vers une chimiothérapie plus efficace et mieux tolérée, Pharm. Hosp, vol.94, pp.35-41, 1988.

J. P. Aymard, R. Ferry, P. Netter, A. Ballaud, and F. Streif, Toxicité cardiaque des alcaloïdes de la pervenche, étude critique de la littérature, Thérapie, vol.40, pp.361-364, 1985.

B. Halliwell and J. M. Gutteridge, Role of free radicals and catalytic metal ions in human diseases: an overview, Methods in Enzymology, vol.186, pp.1-85, 1990.

J. Emerit, J. Fechner, A. Galli, J. P. Clavel, and F. Congy, Les radicaux libres dérivés de l'oxygène et la peroxydation lipidique. Rôle en biologie et en physiopathologie. Presse méd, vol.15, pp.751-754, 1986.

J. M. Clark, The toxicity of oxygen, Am. Rev. Resp. Dis, vol.110, pp.40-50, 1974.

C. Enrique, Biochemistry of oxygen toxicity, Annu. Rev. Biochem, vol.58, pp.79-89, 1989.

N. Koukay, Rôle du zinc et du sélénium dans-la génération des radicaux libres lors des accidents ischémiques du myocarde, 1989.

, The biology of oxygen radical, Science, vol.201, pp.875-880, 1978.

G. T. Gabit and B. M. Barior, The oxygen forming oxidase responsible for the respiratory burst in human neutrophils, J. Biol. Chem, vol.254, pp.9070-9074, 1979.

D. J. Hearse, A. S. Manning, T. M. Downey, and D. M. Yellon, Xanthine oxidase: A critical mediator of myocardial injury during ischemia and reperfusion, Acta. Physio. Scand, vol.548, pp.75-78, 1986.

A. Favier, Interêt des marqueurs de la peroxydation lipidique, Comptes rendus des XIIIèmes journées nationales de biologie. Lyon, pp.45-53, 1990.

T. F. Slater, Free radical mechanisms in tissue inury, Biochem. J, vol.222, pp.1-15, 1984.

H. Kasaï and S. Nishimura, Hydroxylation of guanine in nucleosides and DNA at the C-8 position by heated glucose and oxygen radical forming agents, Environ. Health. Perspect, vol.67, pp.111-117, 1986.

J. M. Gutteridge and B. Halliwell, The measurement and mechanism of lipid peroxidation in biological systems, Trends Biochem. Sei, vol.15, issue.4, pp.129-135, 1990.

D. Chiu, F. Kuypers, and B. Lubin, Lipid peroxidation in human red cells, Seminars in hematology, vol.26, issue.4, pp.257-276, 1989.

C. Dillard and L. Tappel, Lipid peroxidation products in biological tissues. Free Rad, Biol. Med, vol.7, pp.193-196, 1989.

B. Chance, H. Sies, and A. Boveris, Hydroperoxide metabolism in mammalian organs, Physiol. Reviews, vol.59, issue.3, pp.527-604, 1979.

C. Deby and J. Pencemail, Toxicité de l'oxygène, radicaux libres et moyens de défense, Presse Méd, vol.31, pp.1468-1473, 1986.

F. Ursini, M. Mairorino, and C. Gregolin, The selenoenzyme phospholipide hydroperoxide glutathione peroxidase, Biochem. Bioph. Acta, vol.839, pp.62-70, 1985.

A. E. Serbinov, V. Kafan, D. Rand, and L. Packer, Free radical recycling and intramembrane mobility in the antioxydant properties of alpha-tocopherol and alphatocotrienol. Free Rad, Biol. Med, vol.10, pp.263-275, 1991.

S. G. Kenneth, R. Channa, and W. Richard, Reduced glutathione effects on alphatocopherol concentrations of rat li ver microsomes undergoing NADPH-dependent lipid peroxydation, Lipids, vol.24, issue.11, pp.909-914, 1989.

B. Halliwell and J. M. Gutteridge, Oxygen radicals and the nervous system, Trends. Neurosci, vol.8, pp.22-26, 1985.

G. W. Burton and K. V. Ingold, Beta-caroten : an unusual type of lipid antioxidant, Science, vol.224, pp.569-573, 1984.

L. J. Machlin and A. Bendich, Free radical tissues damage : protective role of antioxidants nutrients, FASEB J, vol.1, pp.441-445, 1987.

H. Kappus and H. Sies, Toxic drug effects associated with oxygen metabolism : Redox cycling and lipid peroxidation, Experientia, vol.37, issue.12, pp.1233-1358, 1981.

G. Powis, Free radical formation by antitumor quinones. Free Rad, Biol. Med, vol.6, pp.63-101, 1989.

S. Sato, M. Iwaizumi, K. Handa, and Y. Tamura, Electron spin resonance study on the mode of generation of free radicals of daunomycin, adriamycin and carboquone in NADPH microsomal system, Gann, vol.68, pp.603-608, 1977.

J. Cummings, The molecular pharmacology of Doxorubicin in vivo, Eur. J. Cancer, vol.27, issue.5, pp.532-535, 1991.

B. Kalyanaraman, K. M. Morehouse, and R. P. Masson, An electron paramagnetic resonance study of the interaction between the adriamycin semiquinone, hydrogen peroxide, iron-chelators, and radical scavengers, Arch. Biochem. Biophy, vol.283, issue.1, pp.164-170, 1991.

B. Kalyanaraman, R. C. Sealy, and B. K. Sinha, An electron spin resonance study of of the reduction of peroxydes by anthracyclines semiquinones, Biochem. Biophys. Acta, vol.799, pp.270-275, 1984.

G. Minotti, M. Di-gennaro, D. Granone, and P. , Possible source of iron for lipid peroxidation, Free Rad. Res. Comms, pp.99-106, 1991.

B. Hasinof, Self reduction of the iron(III)-doxorubicin complex. Free Rad, Biol. Med, vol.7, pp.583-593, 1989.

J. Takahashi-naohiro-schreiber, V. Fischer, and R. Mason, Formation of glutathione-conjugated semiquinones by the reaction of quinones with Glutathione: An ESR study, Arch. Biochem. Biophys, vol.252, issue.1, pp.41-48, 1987.

B. D. Hassinof, J. P. Davey, and P. J. O'brien, The Adriamycin (doxorubicin)-induced. inactivation of cytochrome oxydase on the presence of iron and coper, Xenobiotica, vol.19, issue.2, pp.231-241, 1989.

H. Berg, G. Hom, and V. Luthardt, Interaction of anthracycline antibiotics with biopolymers, polarographic behavior and complexes with · DNA, Bioelectrochem. Bioenerg, vol.8, pp.537-558, 1981.

J. R. Mundi, B. K. Sinha, L. Gianni, and C. E. Meyers, Hydroxyl radical production and DNA damage induced by anthracyclines-iron complex, FEBS Lett, vol.172, pp.226-230, 1984.

L. H. Doroshow, S. Akman, S. Esworthy, F. F. Chu, and T. Durbe, Doxorubicin resistance conferred by selective enhancement of intracellular glutathione peroxydase of superoxide dismutase content in human MCF-7 breast cancer cells, Free Rad. Res. Comms, pp.1-10, 1991.

C. A. Pritsot, M. Sokoloff, and D. L. Gustafson, PZ-51 (Ebselen) in vivo protection against Adriamycin-induced mouse cardiac and hepatic lipid peroxidation and toxicity, Biochem. Pharmacol, vol.44, issue.4, pp.839-841, 1992.

C. C. Winterboum, G. F. Vile, and H. P. Monteiro, Ferritin, lipid peroxidation and redox-cycling xenobiotics, Free Rad. Res. Comms, pp.107-114, 1991.

. Sl, C. Coudray, S. Mouhiedine, M. J. Richard, J. Arnaud et al., Effect of adriamycin on chronic cardiotoxicity in selenium deficient rats, Basic Res. Cardiol, vol.87, pp.173-183, 1992.

F. V. Glenn and C. C. Winterboum, Inhibition of adriamycin-promoted microsomal lipid peroxidation by f3-caroten a-tocopherol and retinol at high and low oxygen partial pressures, FEBS Lett, vol.238, issue.2, pp.353-356, 1988.

P. Sangeetha, U. N. Das, R. Koratkar, and P. Suriaprabha, Increase in free radical generation and lipid peroxidation following chemotherapy in patients with cancer. Free Rad, Biol. Med, vol.8, pp.15-19, 1990.

M. Faber, H. Hida, C. Coudray, M. Mousseau, and A. Favier, Lipid peroxidation products and trace elements statuts in patients with cancer before and after chemotherapy including Adriamycin, Biol. Trace Elem. Res, 1993.

. Ss, M. N. Benchekroun, B. K. Sinha, and J. Robert, Doxorubicin induced oxygen free radical formation in sensitive and doxorubicin-resistant variants of rat glioblastoma cell lines, FEBS, vol.322, issue.3, pp.295-298, 1993.

B. K. Sinha and E. G. Mimnaugh, Free radicals and anticancer drug resistance : oxygen free radicals in the mechanism of drug cytotoxicity and resistance by certains tumors. Free Rad, Biol. Med, vol.8, pp.567-581, 1990.

. S7, J. H. Dorochow, and K. J. Davis, Redox cycling of anthracyclines by cardiac mitochondria, J. Biol. Chem, vol.261, issue.7, pp.3068-3074, 1986.

. W. S8.-lown, H. Chen, and J. A. Plambeck, Further studies on the generation of reactives oxygen species from activated anthracyclines and the relationship to cytotoxic action and cardiatoxic effects, Biochem. Pharmacol, vol.31, issue.4, pp.575-581, 1982.

. S9, G. Vile, and C. Winterboum, Thiol oxidation and inhibition of Ca-ATPase by Adriamycin in rabbit heart microsomes, 1990.

C. Meyers, W. Mc-guire, and R. Young, Adriamycin: Ameliorationn of toxicity by a-tocopherol, Cancer treat. Rep, vol.60, issue.7, pp.961-962, 1978.

K. M. Tewey, T. C. Rowe, B. D. Halligan, and L. F. Lui, Adriamycin-induced DNA damage mediated by mamalian DNA Topoisomerase II, Science, vol.226, pp.466-468, 1984.

G. R. Fisher and L. H. Patterson, DNA strand breakage by peroxidase-activated mitoxantrone, J. Pharm. Pharmacol, vol.43, pp.65-68, 1991.

L. H. Patterson, B. M. Gandecha, and J. R. Brown, -hydroxyethyl) amino}-9,10-anthracendione, an anthraquinone antitumor agent that does not cause lipid peroxidation in vivo, comparison with daunorubicin, Biochem. Biophy. Res. Comm, vol.1, issue.2, pp.399-405, 1983.

B. A. Sasville, J. Peisach, and B. Horwitzs, Effect of chelating agent and metal ions on the degradation ofDNA by Bleomycine, Biochemistry, vol.17, pp.2740-2754, 1978.

. 6s, M. E. Scheulen, H. Kappus, D. Thyssen, and C. G. Scmidt, Redox cycling of Fer(III)-Bleomycin by NADPH-Cytochrome P-450 reductase, Biochem. Pharmacol, vol.24, issue.30, pp.3385-3381, 1981.

V. Favaudon, On the mechanism of reductive activation in the mode of action of some anticancer drugs, Biochimie, vol.64, pp.457-475, 1982.

P. J. Smith, Ferrous iron-mediated enhancement of DNA damage and recovry potential in Bleomycin treated humans ce11s, Biochem. Pharmacol, vol.4, issue.36, pp.475-480, 1987.

W. M. Tom and M. R. Montgomery, Bleomycin toxicity: alterations in oxidative metabolism in lung and liver microsomal fractions, Biochem. Pharmacol, vol.29, pp.3239-3244, 1980.

L. Ledwozym, Protective effect of liposomes-entrapped superoxide dismutase and catalase on bleomycin-induced lung injury in rats, Acta Vet. Hung, vol.39, pp.215-224, 1991.

A. C. Sartoelli, The role of mitomycin antibiotics in the chemotherapy of solid tumors, Biochem. Pharmacol, vol.1, issue.35, pp.67-69, 1986.

R. N. Bachur, S. L. Gordon, and M. V. Gee, A general mechanism for microsomal activation of quinones anticancer agents to free radicals, Cancer Res, vol.38, pp.1745-1750, 1978.

M. A. Graham, R. J. Riley, and D. J. Kerr, Drug metabolism in carcinogenesis and cancer chemotherapy, Pharmacol. Ther, vol.51, pp.275-289, 1991.

J. M. Gutteridge, G. J. Quinlan, and S. Wilkins, Mitomycin C induced deoxyribose degradation inhibited by superoxide dismutase, FEES, vol.1, issue.167, pp.37-41, 1984.

D. Seigel, N. W. Gibson, and D. Ross, Metabolism of mitomycin C by DTdiaphorase, role in mitomycin induced DNA damage and cytotoxicity in human colon carcinoma cells, Cancer Res, vol.50, pp.7483-7489, 1990.

A. M. Dulhanty and G. F. Whitmore, Chinese hamster ovary cell lines resistant to mitomycin C under aerobic but not hypoxie conditions are deficient in DT-diaphorase, Cancer Res, vol.51, pp.1860-1865, 1991.

H. F. Bligh, A. Bartoszec, C. N. Robson, and I. D. Hickson, Activation of mitomycin C by NADPH-cytochrome P-450 reductase, Cancer Res, vol.50, pp.7789-7792, 1990.

C. L. Artega, D. L. Kisner, A. Goodman, V. Hoff, and D. D. , Elliptinium, a DNA agent with broad antitumor activity in a human tumor cloning system, Eur.J. Cancer Clin. Oncol, vol.23, pp.1621-1646, 1987.

C. Auclair, K. Hyland, and C. Paoletti, Autoxidation of the antitumor drug 9-hydroxyellipticine and its derivatives, J. Med. Chem, vol.26, pp.1438-1444, 1983.

B. Monsarrat, M. Maftouh, and G. Meunier, oxidative biotransformation of the antitumor agent elliptinium acetate. Structural characterization of its human and rat urinary métabolite, J. Pharm. Biomed. Anal, vol.5, pp.341-345, 1987.

M. Maftouh, Y. Amiar, and F. C. Picard, Metabolism of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate in isolated rat kidney cells, Biochem. Pharmacol, vol.34, p.427, 1985.

C. Dadoun and G. R. Viotte, Celliptium induced nephrotoxicity and lipid peroxidation in rat renal cortex, Cancer Chemother. Pharmacol, vol.27, pp.178-186, 1990.

N. Thomas, G. R. Viotte, M. D. Rothender, H. Eserbauer, and J. P. Fillastre, Time course study of lipid peroxidation induced by N2-methyl-9-hydroxyellipticinium acetate or Celliptium in rat renal cortex, Pharmacol. Toxicol, vol.69, pp.112-116, 1991.

J. E. Mcginness, P. H. Proctor, and G. A. Demopoulos, Amelioration of cis platinium induced nephrotoxicity by orgotein (Superoxide dismutase), Physiol.Chem. Phys, vol.10, pp.267-272, 1978.

J. Hannemann and K. Baumann, Cisplatin-induced lipid peroxidation and decrease of gluconeogenese in rat kidney : Different effects of antioxidants and radical scavengers, Toxicology, vol.51, pp.119-132, 1988.

A. Sodhi and P. Gupta, Increased release of hydrogen peroxide and superoxide anion by murine macrophage in vitro after cisplatin treatement, Int. J. Immunopharmacol, vol.8, p.709, 1986.

G. Bompart, Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drug-metabolizing enzymes activities in rat kidney cortex, Toxicology Letters, vol.48, pp.193-199, 1989.

G. Bompart, Cisplatin-induced changes on cytochromes P-450, lipid peroxidation and some P-450 related specific catalytic activities in rat liver, J. toxicol. clin. exp, vol.10, issue.6, pp.375-383, 1990.

J. Poupon, Cisplatinium and free radicals, Comptes rendus du 4th International Congress on Trace Elements in Medecine and Biology. Trace elements and free radicals in oxydative diseases, 1993.

D. R. Mans, M. V. Lafleur, E. J. Westmijze, and J. M. Vanmaanen, Formation of different reaction products with single and double stranded DNA by the ortho-quinones and the semiquinones free radical of etoposide (VP-16-223), Biochem. Pharmacol, vol.11, issue.42, pp.2131-2139, 1991.

N. Haim, J. Nemec, J. Roman, and B. K. Sinha, In vitro metabolism of etoposide by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins, Biochem. Pharmacol, vol.4, issue.36, pp.527-537, 1987.

G. Powis, E. M. Hodnett, K. S. Santone, L. See, K. Medler et al., The role of metabolism and redox cycling in the cytotoxicity of antitumor quinones, quinoneimines, and quinondiimines, Cancer Res, vol.47, pp.2363-2370, 1987.

R. K. Murray, D. K. Granner, P. A. Mayer, R. K. Murray, and V. Rodwell, Biomolécules et méthodes biochimiques, Précis de biochimie. les presses de l'Université Laval, vol.7, pp.4-12, 1992.

M. J. Richard, P. Guiraud, J. Meo, and A. Favier, High performance liquid chromatographie separation of malondialdehyde-thiobarbituric acid adduct in biological materiels using a commercially available reagent, J. Chromatogr, vol.577, pp.9-18, 1992.

R. Heath and A. Tappel, A new sensitive essay for the mesurement of hydroperoxides, Anal. Biochem, vol.76, pp.184-191, 1976.

H. Hida and . Dea-de-génie-biologique, Mise au point d'une méthode de dosage des hydroperoxydes organiques plasmatique, 1991.

O. H. Lowry, N. J. Rosbrough, A. L. Parr, and R. J. Randal, J. Biol. Chem, vol.193, p.265, 1951.

A. Sevanian, K. Nordenbrand, E. Kim, L. Ernster, and P. Hochstein, Microsomal lipid peroxidation: the role of NADPH-Cytochrome P-450 reductase and cytochrome P-450. Free Rad, biol. Med, vol.8, pp.145-152, 1990.

H. Kappus, Overview of enzyme systems involved in bioreduction of drugs and redox cycling, Biochem. Pharmacol, vol.35, issue.1, pp.1-6, 1986.

E. G. Mimnaugh, M. Trush, and T. Gram, Stimulation by adriamycin of rat heart and liver microsomal NADPH-dependent lipid peroxidation, Biochem. Pharmacol, vol.30, issue.20, pp.2797-2804, 1981.

M. J. Turner, D. B. Everman, S. P. Ellington, and C. Fields, Detection of free radicals during the cellular metabolism of adriamycin. Free Rad, biol. Med, vol.9, pp.415-421, 1990.

G. Minotti, Adriamycin-dependent release of iron from microsomal membranes, Arch. Biochem. Biophy, vol.286, pp.398-403, 1989.

T. Miura, S. Muraoka, and T. Ogiso, Lipid peroxidation of rat erythrocyte membrane induced by adriamycin-Fe3+, Pharmacol. Toxicol, vol.69, pp.296-300, 1991.

G. Minotti, NADPH and adriamycin-dependent microsomal release of iron and lipid peroxidation, Arch. Biochem. Biophy, vol.277, issue.2, pp.268-276, 1990.

E. H. Jeffery, The effect of zinc on NADPH oxidation and monooxygenase activity in rat hepatic microsomes, Mol. Pharmacol, vol.23, pp.467-473, 1983.

M. Chvapil, J. N. Ryan, S. L. Elias, and Y. M. Peng, Protective effect of zinc on carbon tetrachloride-induced liver injury in rats, Exp. Mol. Pharmacol, vol.19, pp.186-196, 1973.

J. F. Sullivan, . M. Jetton, and H. K. Hahn, Enhanced lipid peroxidation in liver microsomes of zinc-deficientrats, Am. J. Clin. Pathol, vol.33, pp.51-56, 1980.

J. Butler and B. M. Hoey, Are reduced quinones necessarily involved in the antiyumor activity of quinone drugs?, Br. J. Cancer, vol.55, pp.53-59, 1987.