Prednisone is genotoxic in mice and Drosophila melanogaster
Introduction
Immunosuppressive drugs are widely used to prevent graft rejection in patients with solid organ transplant (SOT) and to improve lifespan and quality in patients with autoimmune diseases [1,2]. This class of drugs inhibits cell division, reduces the activation or efficacy of the immune system, and presents anti-inflammatory properties [3]. Since patients with SOT and autoimmune diseases require lifelong therapy, these drugs often demonstrate side effects, and patients must be monitored to decrease the risks associated with their treatment [4].
Several studies have correlated the use of these drugs with the increasing risk of tumor occurrence and growth in patients undergoing immunosuppressive therapy [[5], [6], [7]]. Corticosteroids, the most commonly prescribed class of immunosuppressants [8], have shown genotoxic and cytotoxic activity in different in vitro and in vivo studies [9,10]. Moreover, the use of corticosteroids has been associated with an increased occurrence of cancer in patients with SOT, although their contribution to this process is still unclear [11]. Furthermore, cancer is the second leading cause of death in patients with SOT [12], and patients with renal transplants have an increased cancer incidence (three–five times higher) compared to the general population, mainly developing skin cancer and lymphomas [13].
Prednisone (PD) is one of the most commonly recommended corticosteroids in immunosuppressive therapy; it regulates the immunological system by binding to DNA and consequently blocking inflammatory mediators and cell migration and promoting apoptosis of lymphoid cells [3]. Several adverse effects resulting from the use of PD have been reported, such as hypertension, hyperglycemia, osteoporosis, peptic ulcer, adrenal insufficiency, and glaucoma [4]. In addition, a previous study showed that 52.5 % of patients with renal transplants using PD combined with azathioprine developed some kind of cancer [13].
Despite the widespread use of PD by patients with SOT and autoimmune diseases, there are only a few studies on its genotoxic effects [14]. It is known that the development of neoplasia is correlated with genotoxic action [15]. Thus, it is imperative to evaluate the genotoxic activity of PD.
Therefore, the present study aimed to assess the genotoxic and cytotoxic activity of PD using the SMART/wing assay in Drosophila melanogaster and the micronucleus test and comet assay in mouse bone marrow cells. Moreover, we also evaluated the toxic effects of PD in mouse organs using histopathology analysis.
Section snippets
Chemicals
For the SMART/wing test, instant potato purée medium from Yoki Alimentos S/A (São Bernardo do Campo, Brazil) was used. Nipagin was purchased from LabSynth (Diadema, Brazil) and pure bacteriological agar from Digilab (Piracicaba, Brazil). For the in vivo protocols, fetal bovine serum was obtained from Laborclin (Campinas, Brazil), absolute methanol, paraformaldehyde, absolute alcohol, xylol, paraffin, and hematoxylin-eosin (HE) and Giemsa dyes were purchased from Doles (Goiânia, Brazil), and
Toxicity (SMART/wing)
The survival curves after PD treatment are shown in Fig. 1. For both crosses (ST and HB), PD showed significant toxicity in Drosophila (p < 0.05) only at the highest concentration tested (6 mg/mL of PD). The groups treated with other concentrations (0.375, 0.75, 1.5, and 2 mg/mL PD) did not show a significant decrease (p > 0.05) in the number of survivors, as the survival rate at these concentrations was greater than 70 %.
Genotoxicity (SMART/wing)
The results for the marker trans-heterozygous (MH) and balancer
Discussion
Corticosteroids are a class of steroid hormones that are used for chronic treatment in patients with SOT and autoimmune diseases. Despite their effectiveness, the chronic use of corticosteroids is associated with several side effects and an increased occurrence of cancer [11,12]. Among the most recommended corticosteroids, PD has been widely used to suppress the immune system and to reduce inflammation. However, few studies have evaluated the genotoxicity of PD, which could present important
Funding
This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Transparency document
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
We would like to thank the Universidade Federal de Goiás (UFG) for their assistance.
References (51)
- et al.
Organ transplantation: historical perspective and current practice
Br. J. Anaesth.
(2012) Immunosuppressive therapy in transplantation
Nurs. Clin. North Am.
(2016)- et al.
Immunosuppressive drugs and cancer
Toxicology
(2003) - et al.
In vitro and in vivo genetoxicity evaluation of hormonal drugs. II. Dexamethasone
Mutat. Res. Mol. Mech. Mutagen.
(1994) - et al.
Genotoxicity and cancer
Advers. Eff. Eng. Nanomater.
(2012) - et al.
Comparison of high versus low–medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis
Autoimmun. Rev.
(2015) - et al.
In vivo genotoxicity evaluation of efavirenz (EFV) and tenofovir disoproxil fumarate (TDF) alone and in their clinical combinations in Drosophila melanogaster
Mutat. Res. Toxicol. Environ. Mutagen.
(2017) - et al.
Recombinagenic activity of four compounds in the standard and high bioactivation crosses of the wing spot test in Drosophila melanogaster
Mutat. Res. Mutagen. Relat. Subj.
(1996) - et al.
Tables for determining the statistical significance of mutation frequencies
Mutat. Res. Mol. Mech. Mutagen.
(1970) - et al.
Statistical methods to decide whether mutagenicity test data from Drosophila assays indicate a positive, negative, or inconclusive result
Mutat. Res. Mutagen. Relat. Subj.
(1988)
The micronucleus test methodological aspects
Mutat. Res. Mol. Mech. Mutagen.
A simple technique for quantitation of low levels of DNA damage in individual cells
Exp. Cell Res.
The genotoxicity of the anti-cancer drug mitoxantrone in somatic and germ cells of Drosophila melanogaster
Mutat. Res. Toxicol.
The genotoxicity of chromium(VI) oxide in the wing spot test of Drosophila melanogaster is over 90% due to mitotic recombination
Mutat. Res. Mol. Mech. Mutagen.
Dna damage and repair
Leibel Phillips Textb. Radiat. Oncol.
A proximity ligation-based method for quantitative measurement of D-loop extension in S. cerevisiae
Methods Enzymol
Role of homologous recombination in carcinogenesis
Exp. Mol. Pathol.
Dose–response and threshold-mediated mechanisms in mutagenesis: statistical models and study design
Mutat. Res. Toxicol. Environ. Mutagen.
The in vivo rodent micronucleus assay
Genet. Toxicol. Test.
The synergistic effects of vanillin on recombination predominate over its antimutagenic action in relation to MMC-induced lesions in somatic cells of Drosophila melanogaster
Mutat. Res. Genet. Toxicol. Environ. Mutagen.
Human autoimmune diseases: a comprehensive update
J. Intern. Med.
Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation
Clin. Pharmacokinet.
Cancer risk following organ transplantation: a nationwide cohort study in Sweden
Br. J. Cancer
Safety of drugs used for the treatment of Crohn’s disease
Expert Opin. Drug Saf.
Minireview: glucocorticoids in autoimmunity: unexpected targets and mechanisms
Mol. Endocrinol.
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