Francis J. Peterson

Prevention of Acetaminophen and Cocaine Hepatotoxicity in Mice by Cimetidine Treatment

Hepatotoxicity occurs in animals after administration of large doses of acetaminophen and cocaine and is thought to result from production of reactive metabolites of these parent drugs by cytochrome P450. Because cimetidine binds to cytochrome P450 and inhibits hepatic drug metabolism in both humans and animals, we determined the effects of cimetidine coadministration on acetaminophen and cocaine hepatotoxicity in mice. Marked elevations of serum glutamic pyruvic transaminase and severe pericentral hepatocellular necrosis occurred in animals receiving intraperitoneal doses of 350 mg/kg acetaminophen or 35 mg/kg cocaine, while minimal serum glutamic pyruvic transaminase elevations and liver necrosis were seen in animals who also received 100 mg/kg cimetidine 1 h before and 1 h after administration of either acetaminophen or cocaine. Consistent with the hypothesis that these in vivo protective effects resulted from interaction with cytochrome P450, cimetidine inhibited in vitro hepatic microsomal metabolism of cocaine. However, despite its protective effect against acetaminophen-induced hepatic injury, concomitant administration of cimetidine did not significantly affect plasma pharmacokinetics of acetaminophen, prevent depletion of hepatic glutathione after acetaminophen administration, or alter in vivo covalent binding of [3H]acetaminophen to hepatic proteins. These studies suggest that current theories regarding production of acetaminophen-induced liver damage require reexamination. The possibility that cimetidine treatment might be useful in preventing hepatic damage due to acetaminophen and other hepatotoxins in humans is intriguing and also warrants consideration.

The formation of an azo anion free radical metabolite during the microsomal azo reduction of sulfonazo III

Abstract An ESR spectrum is observed during the anaerobic incubation of the diazonaphthol dye sulfonazo III, with rat hepatic microsomes and NADPH. This spectrum is characterized by a partially resolved 17-line hyperfine pattern and g = 2.0043, as is consistent with the spectrum of an azo anion free radical, [R-N-N-R′] • . Oxygen, which strongly inhibits microsomal azoreductase, destroys the ESR signal. The oxidation of the azo anion radical metabolite by oxygen to the parent azo dye may account for the oxygen inhibition of microsomal azoreductase.

THE EFFECT OF SELENIUM AND VITAMIN E DEFICIENCY ON THE TOXICITY OF NITROFURANTOIN IN THE CHICK

Publisher Summary This chapter discusses the effect of selenium and vitamin E deficiency on the toxicity of nitrofurantoin in chick. Nitrofurantoin (N-[5–nitro–2–furfurylidine]–l–amino–hydantoin) is a commonly used urinary tract antimicrobial drug. It has been implicated in a number of drug-induced toxicities, the most common of which is associated with pulmonary injury. Recent studies suggest that the acute toxicity of this drug is mediated by an oxidative stress resulting from the futile reductive metabolism of the drug. In the study described in the chapter, the nitro compound is reduced to the nitro aromatic anion free radical, which is, then, re-oxidized by molecular oxygen regenerating the parent compound and forming superoxide. Superoxide, then, disproportionates to form hydrogen peroxide and ultimately the hydroxyl radical. One line of defense for the aerobic organism against these activated forms of oxygen is the selenium dependent glutathione peroxidase. The chapter explains that the toxicity of nitrofurantoin in the 10–12 day old chick is increased by decreasing the activity of this enzyme. In this animal model, it is found that vitamin E affords no protection against the toxicity of this nitro drug. Data supports the hypothesis that the toxicity of nitrofurantoin in vivo is because of activated forms of oxygen.