Odoardo Tofanetti

Participation of lipid peroxidation in the loss of hepatic drug-metabolizing activities in experimental fascioliasis in the rat

Fascioliasis causes a dramatic decrease in drug-metabolizing ability of the hepatic monooxygenase (MFO) and glucuronosyltransferase (GT) enzyme systems in the rat. The present study was undertaken to determine whether lipid peroxidation is involved in the enzymatic loss. Peroxidative damage of membrane lipids (as assessed by the tissue content of malonic dialdehyde, MDA, and the diene conjugation absorption in microsomal membranes) was found to occur over the entire course of the liver infection (concomitant to a decrease in glutathione levels), and to different degrees in relation to the various steps of the parasite cycle. The onset (MDA six times the controls; delta E 1% = 1.55 at the 20th day) coincides with the beginning of the loss of MFO (-30%) and GT (-20% at the 20th day), and peaks between the 30th and 40th day (MDA eight times the controls; delta E 1% = 1.96), when the loss in the enzyme activities is maximal (MFO - 60/70%; GT - 65/95%). There was a strict correlation at all the observation times between the extent of lipid peroxidation and the decrease in drug metabolizing ability: this supports the view that lipid peroxidation is the major agent in the impairment of MFO and GT enzyme activities, and very likely in the initiation of the pathological degeneration of the liver tissue. As evidenced by histological examination, the phagocytic response of the liver tissue to the parasite invasion and growth leads to oxidative stress, which is the causative agent in the initiation and development of lipid peroxidation.

Involvement of serotoninergic neurons in the hyperthermic response to dopaminergic agonists.

Summary The hyperthermic effect induced by three different dopamine (DA) agonist drugs (d-amphetamine), apomorphine and 2-Br-α-ergocryptine) has been investigated in rabbits with functional impairment of central serotoninergic system. Pretreatment with either p-chlorophenylalanine (PCPA) or selective destruction of serotoninergic nerve terminals by 5,6-dihydroxytryptamine (5,6-DHT) strongly inhibited the hyperthermic effect of all three DA agonists, suggesting a modulatory role of the serotoninergic system in the hyperthermic effect induced by the latter drugs. By contrast PCPA or 5,6 DHT were ineffective in modifying the gnawing behaviour induced by the three DA agonists. The possibility of the existence of a functional link between dopaminergic and serotoninergic neurons in the rabbit brain confined to pathways involved in the regulation of body temperature but not to those involved in the control of stereotyped behaviour is envisaged.

Carboxylic metabolites of tiadenol as “proximate” inducers of hepatic peroxisomal β-oxidation activity

Chronic exposure of rats to the hypolipidemic agent tiadenol causes a dramatic dose-dependent increase of peroxisomal beta-oxidation activity. To elucidate which metabolite of the drug is the proximate inducer (tiadenol is eliminated completely in metabolized form after acute administration) we investigated the qualitative and quantitative metabolic profile of the drug at different doses (50, 150, 300 mg/Kg in two-weeks chronically treated rats, in parallel to that of a model compound, tiadenol-disulfoxide, a weak inducer of palmitoyl-CoA oxidation activity. No changes in the biodisposition of tiadenol (and tiadenol-disulfoxide) were found following chronic treatment for all the doses tested. For both the compounds a strict correlation was evidenced between the extent of formation of carboxylic metabolites and their inductive potencies on peroxisomal beta-oxidation activity. This indicates that tiadenol carboxylic metabolites act as the enzymatic effectors.

Effect of various anti-tumor drugs on energetic processes

Abstract Activity of some anti-tumor drugs on respiration and anaerobic glycolysis of Ehrlichs ascites cells and of rat brain homogenates, as well as on respiration of rat liver homogenates as investigated. Cycle-specific drugs, as Bleomycin, Cytosine arabinoside and Hydroxyurea, are inactive on all tissues examined. Peptichemio and BCNU, cycle-aspecific drugs, inhibit respiration and anaerobic glycolysis of tumor cells. VM 26, Daunomycin and Adriamycin are ineffective on anaerobic glycolysis of tumor cells; VM 26 inhibits respiration, whereas Daunomycin at low concentrations and Adriamycin have a stimulating effect.