Cancer Letters

Cancer Letters

Volume 161, Issue 1, 8 December 2000, Pages 1-7
Cancer Letters

Renal toxicity of the carcinogen δ-aminolevulinic acid: antioxidant effects of melatonin

https://doi.org/10.1016/S0304-3835(00)00568-1Get rights and content

Abstract

An increased incidence of cancer in patients suffering from acute intermittent porphyria (AIP) is thought to be related to δ-aminolevulinic acid (ALA) accumulation. Chronic treatment with ALA augmented 8-oxo-7,8-dihydro-2′-deoxyguanosine levels, decreased microsomal and mitochondrial membrane fluidity and increased lipid peroxidation in blood serum. Co-treatment with melatonin completely counteracted the effects of ALA. Melatonin effectively protects DNA and microsomal and mitochondrial membranes in rat kidney from oxidative damage due to ALA. Because of its low toxicity and anticarcinogenic properties, melatonin could be tested as an agent to reduce oxidative damage in patients with AIP.

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.

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