Elsevier

Toxicology

Volume 191, Issues 2–3, 30 September 2003, Pages 153-158
Toxicology

The activities of tissue xanthine oxidase and adenosine deaminase and the levels of hydroxyproline and nitric oxide in rat hearts subjected to doxorubicin: protective effect of erdosteine

https://doi.org/10.1016/S0300-483X(03)00258-0Get rights and content

Abstract

The aim of this experimental study was to investigate the effects of erdosteine, an antioxidant agent, on doxorubicin (DXR)-induced cardio-toxicity through nitric oxide (NO) levels, collagen synthesis, xanthine oxidase (XO) and adenosine deaminase (ADA) activities in rats. Rats were treated with erdosteine (10 mg/kg b.wt. per day, orally) or saline starting 2 days before administrating a single dose of DXR (20 mg/kg i.p.) or saline. At the 10th day of the DXR administration, hearts were removed under anesthesia for biochemical measurements. Enzyme activities as well as OH-proline and NO levels were found to be significantly increased in DXR group compared with the control group. All of the parameters studied except ADA activity were decreased significantly approximating to the control levels upon erdosteine administration. In conclusion, erdosteine seems to be an alternative agent for protection of cardiac tissue against DXR-induced cardio-toxicity through its regulatory effect on XO activity and NO level.

Introduction

Doxorubicin (DXR), an anthracycline antibiotic that causes severe cardiotoxicity, has been believed to induce the toxic effects via oxidative mechanisms (Dalledonne et al., 1993, Quiles et al., 2002, Venditti et al., 1998). The results of DXR-induced cardiotoxicity are disarrangement of the Z-disc structure, the lack of the thin filaments and the disruption of the cytoskeleton architecture (Molinari et al., 1990). DXR causes cellular injury through detrimental effects on DNA, proteins, lipids and other cellular structures. It causes lipid peroxidation, oxidation of adjacent organelles, and DNA (Zhou and Kang, 2000). The myocardial side effect of DXR has been attributed to the ability of the drug to interact with the genome or to promote lipid peroxidation and generation of free radicals (Doroshow, 1983, Myers, 1998).

It was demonstrated that cardiac NO are increased during the development of DXR-induced cardiomyopathy (Sayed-Ahmed et al., 2001). Recent studies suggest that nitric oxide (NO) may have different roles in cardiac function and disease. Basal production of NO modulates contractility of myocardium and regulates blood flow distribution (Varin et al., 1999). In contrast, high levels of NO production, particularly by inducible NO synthase (iNOS), are associated with numerous types of myocardial disease (Haywood et al., 1996, Vejlstrup et al., 1998, Weinstein et al., 2000). The high levels of NO by iNOS induction may further participate in myocardial oxidative damage through peroxynitrite formation by reacting with superoxide anion (Adams et al., 1999). Peroxynitrite is a potent and aggressive cellular oxidant and causes the formation of 3-nitro-l-tyrosine. This modification has been occupied in a diverse array of disease settings, including myocarditis (Kooy et al., 1997, Weinstein et al., 2000).

It was demonstrated that interstitial accumulation collagen in myocardium was high in DXR-treated rats and decreasing the interstitial collagen accumulation was beneficial in preventing DXR-induced myocardial damage (Tokudome et al., 2000). Hydroxylation of proline is one of the important steps in collagen formation, and assessment of hydroxyproline level may give the clue about collagen accumulation in the extracellular matrix (Monboisse and Borel, 1992).

Erdosteine [N-(Carboxymethylthioacetyl)-homocysteine thiolactone], a mucolytic agent, contains two blocked sulfhydryl groups which are released following its metabolic process (Braga et al., 2000, Dechant and Noble, 1996, Yildirim et al., 2003). It is widely used orally in the clinics due to its mucolytic and expectorant properties. Erdosteine itself does not have free thiole group, but its metabolization produces active metabolite with SH group. Only metabolite I of erdosteine reaches high blood levels, and so the activity of erdosteine is generally attributed to metabolite I (Braga et al., 2000). Its active metabolites exhibit free radical scavenging activity through these SH groups (Dechant and Noble, 1996, Gazzani et al., 1989). The aim of this study, therefore, is to investigate the in vivo effects of erdosteine against DXR-induced cardiotoxicity through purin catobolism, NO system and hydroxyproline (OH-P) formation, as an index of collagen synthesis.

Section snippets

Materials and methods

Male Sprague–Dawley rats (60 days old) were used in the experiments. The animals were housed in quiet rooms with 12:12-h light–dark cycle (07:00–19:00 h) and the experiments were performed in accordance with “Guide for the Care and Use of Laboratory Animals, DHEW Publication No. (NIH) 85–23, 1985” and approved by local ethical committee at Medical School of Inonu University.

Rats were randomly assigned to one of the three groups: control untreated rats (n=8); animals treated with single i.p.

Results

The results are summarized in the Table 1. The activities of XO and ADA were increased in DXR group in comparison with control group (P<0.05). Erdosteine treatment with DXR decreased XO activity significantly in comparison with DXR alone group (P<0.05). On the other hand, the activity of ADA was not affected from erdosteine treatment significantly. The level of NO production was higher in DXR group than the other groups (P<0.001). The level of OH-proline was increased in DXR group in comparison

Discussion

We have found that DXR caused increase in all the parameters studied (hydroxyproline, ADA, XO and NO), and erdosteine showed its protective effect by reversing their measurements almost to the control levels except ADA. Under aerobic conditions, the reduction of DXR through redox cycling results in the formation of superoxide anion radicals, which can later generate other reactive oxygen species. Reactive oxygen species generation, through the production of hydroxyl radicals, can lead to

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