Alterations in hepatic peroxidation mechanisms in thioacetamide-induced tumors in rats. Effect of a rhodium(III) complex.
A model of liver hyperplastic noduligenesis was induced in rats in vivo by long-term administration of thioacetamide (TAM; 100 mg/kg day i.p.). Three doses of 50 mg/kg of an antitumoral rhodium(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Blood and liver were obtained from either TAM, Rh(III) complex or TAM plus Rh(III) complex-treated rats in order to determine the interaction of both (tumoral and antitumoral) substances with the biochemical pathways related to glutathione redox cycle, enzyme activities involved in the oxidative stress coupled to the NADPH/NADP pair and enzymes related to the mono-oxygenase P450 system. The results showed that TAM induced an imbalance between the activities of glutathione-coupled enzymes. Glutathione reductase activity increased along with the intoxication, while glutathione peroxidase activity decreased. Alterations in the activity of soluble glutathione peroxidase were parallel to those of catalase. These results, together with decreased activities of enzymes related to cytochrome P450 mono-oxygenase system, NADPH cytochrome P450 reductase and NADH cytochrome b5 reductase, suggest that liver cells are not protected against the peroxidative stress produced by chronic administration of TAM. The Rh(III) complex did not produce significant changes in the parameters assayed when administered alone. When this complex was administered to TAM-treated rats, significant restoration of the following activities was observed: those of NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and malic enzyme), that of glutathione reductase (NADPH-consuming enzyme), NADPH-cytochrome P450 reductase and total catalase. These results, together with others in previous studies, suggest that the altered liver function induced by chronic administration of TAM can be partially restored by this rhodium complex. The mechanisms by which this complex counteracts the TAM-induced changes have not yet been established.
Cascales
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M
Instituto de Bioquimica (CSIC-UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Martín-Sanz
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P
Craciunescu
D G
DG
Mayo
I
I
Aguilar
A
A
Robles-Chillida
E M
EM
Cascales
C
C
D000818:Animals; D002374:Catalase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004334:Drug Administration Schedule; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009249:NADP / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012238:Rhodium / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013853:Thioacetamide / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D009942:Organometallic Compounds; D010545:Peroxides; D013853:Thioacetamide; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D012238:Rhodium; D002374:Catalase; D005979:Glutathione Peroxidase; D010105:Oxygenases; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005723:gamma-Glutamyltransferase; D005978:Glutathione