Administration Of SKF 525-A Research Articles

Crucial role of cytochrome P450 in hepatotoxicity induced by 2,3‐dimethoxy‐1,4‐naphthoquinone in rats

Quinone toxicity is induced by two principal mechanisms: arylation/alkylation and a redox cycle. We have previously shown that increases in intracellular levels of superoxide anion and cell death induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a redox cycling quinone, are enhanced by pretreatment of rat primary hepatocytes with cytochrome P450 inhibitors. This indicates a novel interaction of quinones with cytochrome P450, and is thus worthy of further investigation using an in vivo model. The aim of this study was to examine the effects of cytochrome P450 inhibitors on DMNQ-induced hepatotoxicity in rats. When DMNQ was administered intraperitoneally, the activities of serum alanine aminotransferase and aspartate aminotransferase were found to increase in a dose-dependent manner, indicating that hepatotoxicity was induced by treatment with DMNQ. Pretreatment with the cytochrome P450 inhibitors SKF-525A (SKF), cimetidine and ketoconazole potentiated the DMNQ-induced hepatotoxicity. The blood concentration of DMNQ was not affected by administration of SKF. Pretreatment with the antioxidant α-tocopherol almost completely attenuated the hepatotoxicity induced by DMNQ and by the combination of DMNQ with SKF. Levels of reduced glutathione in the liver were decreased and levels of oxidized glutathione were increased by treatment with DMNQ. These effects were potentiated by pretreatment with SKF. DMNQ-induced lipid peroxidation in the liver was also enhanced by pretreatment with SKF. Taken together, these results indicate that DMNQ-induced hepatotoxicity is augmented by inhibition of cytochrome P450 and that this augmentation is due to the enhancement of oxidative stress.

Pesticide resistance in wild mammals - Mechanisms of anticoagulant resistance in wild rodents -

Warfarin is commonly used worldwide as a rodenticide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. It has been reported that repeated or long-term treatments with this drug cause resistance in wild rodents. However, the mechanism of warfarin resistance in rodents is still not known precisely. Recent studies reported and identified the function of the molecule, vitamin K epoxide reductase complex subunit 1 (VKORC1), which is the main unit of VKOR. An amino acid substitution in VKORC1 is one of the supposed mechanisms of warfarin resistance. An accelerated detoxification system involving cytochrome P450 (CYP) could also cause the rodenticide resistance. Administration of SKF-525A, a potent inhibitor for P450, increased the mortality due to reduction of warfarin metabolism in warfarin-resistant rats. Meanwhile, the appearance of warfarin-resistant rodents has led to the development of the more effective and toxic rodenticide superwarfarin, which is widely used in Europe and the USA. However, animals resistant to this second-generation rodenticide have already been reported in Europe. In this review, we focus on the mechanism and the pleiotropic effects of pesticide resistance in wild rodents.

Effects of SKF 525A, Phenobarbital, and 3-Methylcholanthrene on Ethylene Dichloride Toxicity Following Inhalation Exposure

The effect of cytochrome P-450-dependent metabolism on ethylene dichloride (EDC) toxicity was investigated in mice. Prior to exposure to EDC, groups of male CD-1 mice were pretreated with phenobarbital or 3-methylcholanthrene to induce metabolism. Other mice were administered SKF 525A before EDC exposure to inhibit cytochrome P-450 metabolism. Following the different pretreatments, mice were exposed to EDC at selected concentrations (1000 ppm, 1250 ppm, or 1500 ppm). Exposure to EDC, without pretreatment, produced a dose-dependent increase in mortality at 24 and 48 hours postexposure. This response was enhanced at all concentrations of EDC by phenobarbital pretreatment and attenuated by the administration of SKF 525A. Pretreatment with 3-methylcholanthrene prior to EDC exposure at 1000 ppm also produced an increase in mortality as compared to EDC exposure without pretreatment. Exposure to EDC was associated with an increased kidney weight:body weight ratio. SKF 525A pretreatment prevented the increase in the kidney weight:body weight ratio at an EDC exposure concentration of 1000 ppm. Pathological changes produced in the kidneys of mice exposed to EDC were decreased by SKF 525A pretreatment. These results support the hypothesis that a product of the cytochrome P-450-dependent metabolism of EDC is involved in the toxicity produced following acute inhalation exposure to this chemical.

Effects of drug metabolism inhibitors on butylated hydroxytoluene-induced pulmonary toxicity in mice

The administration of butylated hydroxytoluene (BHT) to mice results in lung cell damage followed by cellular proliferation which was quantitated by measuring the increase in thymidine incorporation into pulmonary DNA. Administration of SKF 525-A or piperonyl butoxide to mice treated with BHT prevented the increase in thymidine incorporation into pulmonary DNA. This effect was dose dependent, with complete protection from 400 mg/kg BHT achieved with 10 mg/kg SKF 525-A or 400 mg/kg piperonyl butoxide. SKF 525-A and piperonyl butoxide completely prevented the BHT-induced increase in pulmonary DNA synthesis even when given 1–2 hr after BHT and a partial protective effect was evident when they were given 6–12 hr after BHT. Pretreatment of mice with cobaltous chloride diminished the BHT-induced increase in thymidine incorporation into pulmonary DNA. Following the in vivo administration of [ 14C]BHT, radioactivity was covalently bound to lung, liver, and kidney macromolecules of both mice, which exhibited BHT-induced lung damage, and rats, which did not. The greatest amount of radioactivity was bound to lung tissue from mice. This binding was prevented by the administration of SKF 525-A and was a linear function of the BHT dose within a range of 50–600 mg/kg. Binding to other tissues from the mouse and all tissues examined in the rat was minimal and unaffected by SKF 525-A. These data suggest that a reactive metabolite of BHT rather than the parent compound produces lung damage in mice.

Prevention of carbon tetrachloride-induced necrosis by inhibitors of drug metabolism—Further studies on their mechanism of action

Liver necrosis caused by CCl 4 is known to be decreased by the administration of SKF 525-A (2-diethylaminoethyl 2,2-diphenylvalerate), Sch 5705 (ethyl 2-diethyl-aminoethyl-2-phenyl-2-ethyl malonate), Sch 5706 [ethyl N-(2-diethylaminoethyl) 2-phenyl-2-ethyl malonate], Sch 5712 (ethyl 2-diethylaminoethyl 2-ethyl-2-butyl malonate), CFT 1201 [2-diethylaminoethyl 2-phenyl (2-propene) 4-penten-1-oate], Lilly 18947 (2,4-dichloro-6-phenyl phenoxyethyl diethylamine) and DPEA (2,4-dichloro-6-phenyl phenoxyethylamine). Although these substances are known to inhibit cytochrome P-450 dependent drug-metabolizing enzymes in liver microsomes, they apparently do not evoke their protective effects by slowing the elimination of CCl 4. In fact, SKF 525-A, but none of the other inhibitors, partially prevents the impairing effects of CCl 4 on cytochrome P-450 in liver. Although SKF 525-A markedly decreased the liver necrosis and the rise in serum isocitrate dehydrogenase (ICD) caused by CCl 4, it only partially prevented the CCl 4-induced decrease in body temperature.

Changes in the neuro-excitability of alcohol-dependent rats undergoing withdrawal as measured by the pentylenetetrazole seizure threshold

Rats that had been intubated intragastrically with alcohol two or three times daily for 7 days exhibited a withdrawal syndrome after the cessation of treatment. On the day of withdrawal pentylenetetrazole (PTZ) seizure thresholds were significantly reduced while an elevation was observed from 1 day to 4 weeks after withdrawal. In addition, multiple convulsions were noted after exposure to PTZ from 1 to 7 days after withdrawal. The elevation in PTZ thresholds is apparently not related to physical dependence since administering alcohol once daily for 14 days resulted in no overt withdrawal syndrome but still led to a significant increase in the PTZ threshold. Also, a possible acceleration in the rate of metabolism of PTZ as a result of chronic administration of alcohol does not appear to contribute significantly to the elevated PTZ thresholds since this effect was not antagonized by the administration of SKF 525A one hour prior to the determination of PTZ thresholds. The data suggest that there exists a number of changes in the neuro-excitability of alcohol-dependent rats not previously described in experimental animals.

Bromobenzene metabolism and hepatic necrosis.

Treatment of rats with Phenobarbital stimulates the metabolism of bromobenzene and potentiates the hepatic necrosis elicited by the hydrocarbon. In contrast, administration of SKF 525-A or of piperonyl butoxide blocks bromobenzene metabolism and prevents the damage to the liver. These results indicate that the hepatotoxic effect of bromobenzene is mediated by a metabolite.

Influence of enzyme induction on the sleeping time of rats.

Hepatic microsomal enzyme systems can be activated by pretreatment with phenobarbital, other barbiturates, ddt, and many other drugs. Contrarily, another compound such as skf 525-a, ethionine, and puromycin can inhibit the same enzymatic mechanisms. The sleep-time periods of albino rats produced by pentobarbital, thiopental, zoxazolamine, ci-581, diazepam, and gamma-hydroxybutyrate were significantly shortened by previous administration of phenobarbital twice daily for four days. However, the duration of action of the same anaesthetics was significantly prolonged when the animals were “pretreated” by the administration of skf 525-a, an inhibiter of liver microsomal enzymes.

MECHANISM OF DEVELOPMENT OF TOLERANCE TO B-DIETHYLAMINOETHYL DIPHENYLPROPYLACETATE (SKF 525-A) IN THE RAT.

SummaryData presented here substantiate the early finding of Cook et al(1) that a tolerance develops to the hexobarbital prolonging effects of SKF 525-A in the rat. It is further shown that the biochemical correlates of this tolerance are an increased biosynthesis of ascorbic acid and an increased liver protein (enzyme) synthesis, which can be blocked by simultaneous administration of DL-ethionine. These observations are consistent with the action of several agents having the ability to stimulate drug metabolism (5). The mechanism of the tolerance, then, may be attributed to an induced metabolic alteration or adaptation to prolonged administration of SKF 525-A. Increased biosynthesis of ascorbic acid in animals repeatedly administered SKF 525-A indicates that impairment of ascorbic acid biosynthesis is not a related factor in the mechanism of action of this drug metabolism inhibitor.

The effects of SKF 525-A on hepatic glycogen and rate of hepatic drug metabolism

The level of hepatic glycogen and rates of certain drug metabolisms were studied after administration of SKF 525-A (β-diethylaminoethyl diphenylpropyl acetate HCl) to adult rats. SKF 525-A inhibits hepatic drug metabolism within 1 hr, and a significant effect is seen up to 24 hr after administration. SKF 525-A lowers hepatic glycogen to a minimum level in 8 to 12 hr. The recovery of hepatic glycogen and rate of hepatic drug metabolism to control values occurs at the same time after administration of SKF 525-A. The effects of SKF 525-A on certain enzymes of hepatic glycogenesis and glycogenolysis were also studied.