Renal toxicity of the carcinogen δ-aminolevulinic acid: antioxidant effects of melatonin
Introduction
Under conditions of undisturbed haem synthesis, δ-aminolevulinic acid (ALA) is essentially undetectable in human blood, but elevated concentrations of this molecule in blood and its accumulation in a number of organs are typically found in patients with acute intermittent porphyria (AIP), lead-poisoning or hereditary tyrosinemia. When given to rats, ALA is taken up by several organs, including the kidneys [1]. ALA, when produced in excess, is an endogenous source of toxic oxygen derivatives [2] which leads to DNA damage and an increased cancer risk. Thus, an almost 2-fold increase in the incidence of cancer generally, and 70-fold increase in primary liver cancer (almost exclusively hepatocellular carcinoma), was reported in AIP patients [3]. Renal carcinoma, however, was not particularly common in these individuals [3]. An increased incidence of cancer in patients suffering from AIP [3] is thought to be related to ALA accumulation.
Well documented are the antioxidative properties and free radical scavenging capacity of melatonin [4], [5], [6], [7], [8], [9], the chief indoleamine produced by the pineal gland. Melatonin effectively protects DNA [10], [11], [12], [13], lipids [5], [14] and proteins [15] from oxidative damage caused by numerous endogenous and exogenous toxicants and is a well known anticarcinogen [16], [17], [18]. The aim of the present study was to examine whether melatonin would protect against oxidative damage to renal DNA and microsomal and mitochondrial membranes caused by carcinogen ALA.
Section snippets
Chemicals
RNase A and T1, proteinase K, nuclease P1 and alkaline phosphatase were purchased from Boehringer Mannheim (Indianapolis, IN), the LPO-586 kit for lipid peroxidation from Calbiochem (La Jolla, CA), 1-[4-(trimethylammonium)phenyl]-6-phenyl-1,3,5-hexatriene p-toluene sulphonate (TMA-DPH) from Molecular Probes (Eugene, OR), and δ-aminolevulinic acid from Sigma (St. Louis, MO). Pure melatonin was a gift from Helsinn Chemicals SA (Biasca, Switzerland). Other chemicals used were of analytical grade
Results
8-oxodGuo levels were significantly higher in rat kidneys collected from animals treated with ALA than those in the kidneys of control or melatonin-treated rats. Melatonin given to animals injected with ALA reduced significantly the increase in 8-oxodGuo levels (Fig. 1).
ALA caused a significant decrease in both microsomal (Fig. 2A) and mitochondrial (Fig. 3A) membrane fluidity (an increase in membrane rigidity) when compared to that of control or melatonin-injected rats. ALA did not increase
Discussion
Multiple injections with ALA, as applied in this study, are believed to mimic the condition of AIP and other disturbances related to ALA accumulation. The dose of ALA used in this study, i.e. 40 mg/kg b.w., results in a blood concentration similar to that observed in patients with porphyrias [1].
The increased oxidation of guanine bases of DNA in the rat kidney caused by ALA treatment is consistent with previous reports on rat kidney and liver [23]. The destructive effects of ALA on DNA may
Acknowledgements
Małgorzata Karbownik was supported by an American Cancer Society International Fellowship for Beginning Investigators. Research was supported in part by a grant from Amoun Pharmaceutical Company.
References (33)
- et al.
Tissue uptake of δ-aminolevulinic acid
Biochem. Pharmacol.
(1975) - et al.
Free radical generation during δ-aminolevulinic acid auto-oxidation induction by hemoglobin and connections with porphyrinopathies
Arch. Biochem. Biophys.
(1989) Oxidative damage in the central nervous system: protection by melatonin
Prog. Neurobiol.
(1998)- et al.
Inhibitory effects of melatonin on ferric nitriloriacetate-induced lipid peroxidation and oxidative DNA damage in the rat kidney
Toxicology
(1999) - et al.
Augmentation of indices of oxidative damage in life-long melatonin-deficient rats
Mech. Aging Dev.
(1999) - et al.
Effects of melatonin on N-nitroso-N-methylurea-induced carcinogenesis in rats and mutagenesis in vitro (Ames test and COMET assay)
Cancer Lett.
(1999) - et al.
Melatonin decreases cell proliferation and transformation in a melatonin receptor-dependent manner
Cancer Lett.
(2000) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
(1976)- et al.
Effect of age-related lipid peroxidation on membrane fluidity and phospholipase A2: modulation by dietary restriction
Mech. Aging Dev.
(1992) - et al.
Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation
FEBS Lett.
(1997)
Hydroxyl radicals are involved in the oxidation of isolated and cellular DNA bases by 5-aminolevulinic acid
FEBS Lett.
DNA damage by 5-aminolevulinic and 4,5-dioxovaleric acids in the presence of ferritin
Arch. Biochem. Biophys.
Oxidative damage of mitochondria induced by 5-aminolevulinic acid: role of Ca2+ and membrane protein thiols
Biochim. Biophys. Acta
Melatonin is a scavenger of peroxynitrite
Life Sci.
Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks
Life Sci.
Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden
Am. J. Epidemiol.
Cited by (40)
Melatonin modulates drug-induced acute porphyria
2016, Toxicology ReportsCitation Excerpt :In the case of controls, Mel, AIA and DDC vehicles were administered. Mel dosage was based on studies about its drug toxicity-reduction and drug protective ability [27,11,13]. Rats were fasted 8 h before and 16 h after intoxication.
Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases
2015, Mechanisms of Ageing and DevelopmentThe Porphyrias
2014, Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth EditionMelatonin and its atheroprotective effects: A review
2014, Molecular and Cellular EndocrinologyMelatonin and mitochondrial dysfunction in the central nervous system
2013, Hormones and BehaviorCitation Excerpt :Melatonin was also effective to maintain the efficiency of OXPHOS and ATP synthesis by increasing the activity of C-I, C-III and C-IV (López et al., 2009). Interestingly, co-treatment with melatonin prevented the decrease in mitochondrial membrane fluidity caused by δ-aminolevulinic acid, which disrupts H+ electrochemical gradient and mPT, in the absence of changes in mitochondrial membrane lipid peroxidation (Karbownik et al., 2000). This effect of melatonin may depend on its capacity to localize in the membrane itself, in a superficial position in lipid bilayers near the polar heads of membrane phospholipids (Ceraulo et al., 1999).