Structural and functional changes in the surface membranes of hepatocytes play a pivotal role in the induction and reversion of some forms of drug-induced cholestasis. To elucidate the mechanism by which S-adenosyl-L-methionine (SAMe) leads to a partial reversion of bile flow impairment caused by ethinyl estradiol (EE), female Sprague-Dawley rats were given oral doses of EE (5 mg per kg per day, for 3 days) with and without simultaneous administration of SAMe (25 mg per kg, 3 times per day, for 3 days). Na+,K+-ATPase activity and membrane microviscosity as measured by fluorescent polarization were assayed in isolated liver plasma membranes (LPMs). SAMe administration to normal and EE-treated rats resulted in a marked increase in Na+,K+-ATPase activity and LPM fluidity. EE alone did not cause any change in the physicochemical properties of the LPMs. Hepatic Mg2+-ATPase and gamma-glutamyl transpeptidase activities were not affected by SAMe alone but increased when SAMe was given together with EE. These data indicate that the interaction of in vivo administered SAMe with hepatocyte plasmalemma and its effect on lipid fluidity and enzymes of the LPMs showed a high specificity and an inverse relationship between Na+,K+-ATPase activity and fluorescence polarization values. Furthermore, modulation of hepatic Na+,K+-ATPase was associated with SAMe-induced protection against bile flow impairment due to EE; however, it was not the causative factor for EE-induced cholestasis under the experimental conditions. These findings suggest that changes in surface membrane structure and function might account in part for the reversal by SAMe of EE-induced impairment of bile secretory function.

Animals↗

PubMedDate not supplied

Enhancement of cardiotoxic effects of beta-adrenergic bronchodilators by aminophylline in experimental animals.

To examine the cardiotoxic interaction between beta-adrenergic bronchodilators and theophylline, we tested the effects of isoproterenol or bitolterol alone and in combinations with aminophylline in experimental animals, both electrocardiographically and histologically. The sc LD50 values for isoproterenol in 4- to 5-month-old, 500-600 g (heavy) and 1.5- to 2-month-old, 150-200 g (small) male Sprague-Dawley rats were 0.6 mg/kg and 1300 mg/kg, respectively, and values for bitolterol were 4 mg/kg and greater than 1800 mg/kg, respectively. Results of the electrocardiographic studies in heavy rats, using the calculated LD20 dosage of isoproterenol with or without pretreatment of aminophylline, demonstrated that both mortality and the arrhythmia-inducing effect of isoproterenol were significantly potentiated by aminophylline but only mortality was increased in small rats. Aminophylline also potentiated the electrocardiographic effects of 1/40 of the LD50 dosage of isoproterenol in heavy rats but did not enhance the effects of bitolterol at this dose level. Potentiation of the arrhythmogenic effect of isoproterenol was also observed in rabbits. The severity of the myocardial lesions produced by isoproterenol or bitolterol in heavy rats was significantly enhanced by aminophylline. The heavy rat appears to be a sensitive model for studying the interaction of these classes of drugs.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Assessment of hepatic function in rabbits with steroid-induced cholestatic liver injury.

Methyltestosterone (MT) or ethinyl estradiol (EE) was administered to adult rabbits for 20 weeks beginning with initial daily doses of 0.4 mg/kg MT and 0.015 mg/kg EE for three weeks, then these dosages were doubled at 3-week intervals to a maximum dosages 6.4 mg/kg and 0.24 mg/kg, respectively. Within 2 weeks, the serum gamma-glutamyltransferase activity of MT and EE treated rabbits was significantly greater than controls and increased progressively throughout the treatment period. Aspartate aminotransferase activity was also increased at 2 weeks and remained so for 17 weeks. Serum alkaline phosphatase was elevated at 2 weeks but thereafter was normal indicating that this enzyme is of no value in detecting steroid-induced hepatic dysfunction. Elevated serum bile acid concentration and prolonged BSP clearance indicated marked hepatic excretory dysfunction at higher dose levels. Histologic abnormalities were observed in the livers of both MT and EE treated rabbits. These lesions were more severe in the EE group in which there was marked bile duct proliferation, mononuclear cell infiltration of portal areas, and perilobular fibrosis. The studies indicate that the rabbit is susceptible to development of hepatic injury when receiving 17 alpha-alkyl substituted steroids and may be a useful animal model for investigations of the pathogenesis of steroid-induced cholestatic liver injury.

Alanine Transaminase↗

PubMedDate not supplied

Effect of cefazolin on aminotransferase activity in the rat.

Cefazolin given sc to male rats in daily doses of 0.5-2 g per kilogram of body weight significantly decreased alanine aminotranferase activity in serum, liver, kidney, heart, and brain 2-4 wk from the beginning of the treatment. Serum aspartate aminotransferase was also reduced, but serum alkaline phosphatase and tissue pyruvate decarboxylase activities remained unaltered. In female rats, daily sc administration of cefazolin at 0.1-1 g/kg also brought about a dose-related reduction of alanine and aspartate aminotransferase activities, which reached statistical significance at high dose levels. The effect of cefazolin at low concentrations was partly reversed by administration of pyridoxal in vivo. Paradoxically, at higher dose levels pyridoxal potentiated the action of cefazolin on serum aminotranferases. The low enzyme activities were elevated by subsequent addition of pyridoxal 5'-phosphate in vitro. Similar results were obtained when rats were treated with isoniazid at daily oral doses of 200 mg/kg; administration of pyridoxal completely restored alanine aminotransferase activity to the normal level within 2 wk. Cefazolin was metabolized in vivo, resulting in some metabolites that probably possessed a hydrazine group, since positive reactions were obtained with p-dimethylaminobenzaldehyde and Fast Blue B salt. The potentiation of decreased aminotransferase activity by pyridoxal indicated, however, some dissimilarity in the effect between isoniazid and cefazolin.

Alanine Transaminase↗

PubMedDate not supplied

Enhancement of acute myocardial lesions by asthma drugs in rats.

Asthma morbidity and mortality have risen significantly in the last 10 years. The reasons for the increase are multifactorial. One proposed explanation is possible myocardial toxicity arising from the use of beta-agonists alone or in combination with methylxanthines. Previous studies have shown that beta-agonists given alone and beta-agonist/methylxanthine combinations given at higher than recommended clinical doses induced dose-related cardiotoxicity and sudden death in rats. The objective of the present study was to determine whether or not beta-agonists given alone and in combination with methylxanthines at recommended clinical doses also induce cardiotoxicity and sudden death in rats. The beta-agonists, isoproterenol hydrochloride (15 micrograms/kg), fenoterol hydrobromide (40 micrograms/kg), and terbutaline hemisulfate (0.4 mg/kg) were given in single sc doses separately and concurrently with the methylxanthines aminophylline hydrate (20 mg/kg) and caffeine (40 mg/kg), which were given up to a susceptible animal model, the heavy Sprague-Dawley rat. beta-agonist-induced myocardial toxicity (necrosis) was observed. The toxicity was enhanced by aminophylline resulting in the sudden death (most likely due to ventricular fibrillation) of some animals. A decrease in serum iron levels was observed in rats of all beta-agonist and/or methylxanthine-treated groups.

Acute Disease↗

PubMedDate not supplied

Correlation of human hepatotoxicants with hepatic damage in animals.

Substances that cause liver damage in humans were identified through a literature search conducted on Toxline and Medline. Using the same search strategy, species other than man were selected, in whom hepatic injury could be attributed to exposure to the identified substances. A total of 38 substances were identified as producing liver damage, manifested by either clinical chemistry or histopathology. The substances included 24 drugs, 9 industrial chemicals, 3 environmental agents, 1 pesticide, and ethanol. Twelve of the 36 compounds have been toxicologically evaluated in man, rodent, and non-rodent. Histopathologic liver damage was reported in all three species for 11 of these compounds. Only carbencillin produced histopathologic damage in man but not in either the rodent or non-rodent. Where clinical chemistry changes were reported for all three species categories, only eight substances induced similar reactions in all three species. Only with two substances did man and rodent react similarly (both positive), while the non-rodent was negative. The two substances were polychlorinated biphenyl (PCB) and tetrachlorethane. In the majority of the cases in which either or both histopathologic or clinical chemistry changes were reported for man or for the rodent or non-rodent, the changes that occurred were qualitatively similar. The rodent was as sensitive a predictor for hepatic effects as the non-rodent. Although it is impossible to predict how liver damage observed in a laboratory animal is correlated with human liver damage, hepatotoxicity in the rodent must be considered as indicative of potential hepatic damage in man.

Animals↗

PubMedDate not supplied

Toxic cardiomyopathies.

Examples of toxic cardiomyopathies of various characteristics are presented. Daunomycin and doxorubicin, antineoplastic drugs, cause multifocal cardiomyopathies and intractable heart failure by cardiotoxic mechanisms; these effects are delayed and related to the cumulative dose. Cobalt caused diffuse vacuolar cardiomyopathy in chronic beer drinkers. The development of fulminant heart failure was the function of factors that increased the adsorption of cobalt or sensitized the myocardium to its cytotoxic effect. Beta-adrenergic receptor stimulant bronchodilators like isoproterenol or vasodilating antihypersensitive drugs like hydralazine are able to produce focal subendocardial necroses. This lesion is due to ischemia brought about by the acute exxagerated pharmacological effects of these compounds.

Animals↗