Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats

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Abstract

In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and γ-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum–DNA adducts (+31%, P<0.05) and percent DNA–DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (−15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.

Introduction

Cisplatin is one of the most active antineoplastic drugs that is particularly used for the treatment of ovarian, testicular and head and neck cancers Van Basten et al., 1997, Thigpen et al., 1994. In spite of its significant antitumor activity, the clinical use of cisplatin is often limited by its undesirable side effects, nephrotoxicity and neurotoxicity being the most severe and dose-limiting ones Mollman et al., 1988, Screnci and McKeage, 1999. Nevertheless, other less frequent toxic effects, as hepatotoxicity, which is frequently observed after administration of high doses of cisplatin, can alter the clinical situation of patients Cersosimo, 1993, Cavalli et al., 1978, Pollera et al., 1987. Many efforts have been made to improve the therapeutic index of cisplatin using pharmacological strategies, such as the administration of chemoprotectors, intensive hydration and hypertonic saline Skinner, 1995, Anand and Bashey, 1993, Pinzani et al., 1994. Unfortunately, some of the compounds used as chemoprotectors also inhibit the antitumor activity of cisplatin, while other therapeutic strategies were not completely efficient in reducing the dose-limiting nephrotoxicity Aamdal et al., 1987, Jones et al., 1991, Abe et al., 1990, Pinzani et al., 1994.

In our previous studies Esposito et al., 1996, Viale et al., 2000, we found evidence for a chemoprotective effect of procainamide hydrochloride against cisplatin-induced nephrotoxicity in mice and rats. This class I antiarrhythmic drug was able to reduce the weight loss and to protect mice against death induced by lethal doses of cisplatin. The combination therapy of procainamide hydrochloride and cisplatin resulted in a significant increase in survival, when drugs were administered either simultaneously i.p. or through different routes of administration (i.p. and i.v.). In rats, procainamide hydrochloride protected from nephrotoxicity when given simultaneously or from 1 h before to 1 h after cisplatin, as confirmed by plasma urea nitrogen and creatinine levels and microscopical analysis of kidney tissue. Moreover, procainamide hydrochloride decreased the urinary excretion of platinum and increased platinum concentration in the kidney of rats. Based on the capability of procainamide hydrochloride to react with cisplatin and its hydrolysis products, we proposed that the antiarrhythmic drug could accumulate in the kidney and coordinate with the anticancer drug forming a less toxic platinum coordination complex, which renders rats less susceptible to cisplatin-induced toxicity.

In the present paper, we studied the protective activity of procainamide hydrochloride on cisplatin-induced hepatotoxicity, in particular, on the level of cellular damage of liver parenchyma. This was determined by measuring plasma glutamic oxalacetic and glutamic pyruvate transaminases, γ-glutamyl transpeptidase and by histochemical analysis of liver tissue. The analysis in liver of total platinum, platinum–DNA adducts, percent interstrand cross-links, procainamide concentration and intracellular platinum distribution was also performed.

Section snippets

Chemicals

Cisplatin and procainamide hydrochloride were purchased from Sigma (St. Louis, MO, USA). When the two drugs were administered to rats as single agents, cisplatin was dissolved in normal saline (0.9% NaCl), while the modulating agent was diluted in distilled water to prepare a 1.25% solution. Since dissolving procainamide hydrochloride in 0.9% NaCl increases the chloride anion concentration of the solution, when both drugs were administered together, they were diluted in appropriate NaCl

Evidence of liver tissue damage

In our experiments, the high dose of cisplatin (7.5 mg/kg) administered to rats caused an evident liver damage characterized by a significant increase of glutamic oxalacetic transaminase [385±105 vs. 143±20 IU/ml in controls] and γ-glutamyl transpeptidase [5.8±1.3 vs. 0.8±0.8 IU/ml in controls] plasma activities. A slight, but not significant, elevation of plasma glutamic pyruvate transaminase [83±27 vs. 50±1 IU/ml in controls] was also observed (Table 1). It is of note that the treatment with

Discussion

It is known that cisplatin is significantly taken up in human liver (Smith and Taylor, 1974); nevertheless, hepatotoxicity rarely occurs. For this reason, this toxic effect has not received much attention and only few articles deal with this aspect. Generally, liver toxicity of cisplatin is characterized by mild to moderate elevation of serum transaminases and, less frequently, by a mild elevation of serum alkaline phosphatase, lactate dehydrogenase, bilirubin and γ-glutamyl transpeptidase

Acknowledgements

This paper is dedicated to Dr. Mauro Esposito who first had the idea to use procainamide as chemoprotector against cisplatin-induced nephrotoxicity. We thank Prof. M. Novi for the critic revision of this paper. This work was in part supported by “Lega Italiana per la Lotta contro i Tumori”, Section of Sanremo, Italy.

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