Chronic renal failure rats are highly sensitive to aristolochic acids, which are nephrotoxic and carcinogenic agents
Introduction
Aristolochic acids (AA) extracted from genus Aristolochia, including 8-methoxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) and 6-nitrophenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAII), are regarded as the principal components of herbal remedies to stimulate the defense mechanism against infections, to treat patients with arthritis, gout, as well as tumors [1], [2], [3], [4], [5]. However, in 1991, AA in slimming capsules was suspected of causing the so-called Chinese herb nephropathy (CHN), a progressive renal fibrosis that was diagnosed in a group of young Belgian women who had all followed the same slimming regimen [6]. Since then, multiple cases of CHN have been sporadically reported worldwide [4], [7], [8] and the potential nephrotoxicity of AA to rodents has also been ascertained in several laboratories [8], [9], [10], [11]. Furthermore, animals treated with AA seemed to be predisposed to develop various tumors [5], [12], [13], [14].
Recent studies have revealed the potential genotoxic mechanisms of AA in rodents, in which AA was metabolized through the nitroreduction pathway to turn into the mutagenic species aristolactam-nitriumion that might form covalent AA–DNA adducts along with deoxyadenosin or deoxyguanosin residues in DNA [15], [16]. Of these, the adenine adducts (dA–AAI and dA–AAII) have been detected not only in the tumors of rodents [15], [16], [17] but also in urethelial tissue of CHN patients [18]. To search for the tumorigenic mechanisms of AA, it has been suggested that the adenine adducts of AA–DNA might mistakenly be incorporated with dAMP during DNA synthesis, thereby leading to an A:T→T:A transversion mutation during the subsequent DNA replication [19], [20]. The A:T→T:A mutation has been identified in the activated H-ras proto-oncogene, specifically at its codon 61 (CAA→CTA), in the tumors of rodents treated with plant extracts containing AA [21], suggesting that the adenine adducts caused by the intake of AA components might bypass the eukaryotic DNA repair machinery.
Although there is increasing evidence demonstrating the nephrotoxicity and carcinogenicity of AA in rodents [13], [22], only a small percentage of participants who followed the similar slimming regimen offered by the same clinical center in Belgium have actually developed CHN or cancers [23]. It has been suggested that the composition difference of AA in the slimming pills due to the batch variation of production might lead to this clinical discrepancy [24], [25]. On the other hand, the impacts of AA administration may greatly depend on each individual physical history. Therefore, in this study, we characterized the outcomes of AA intake in rats some of which had undergone the 5/6 chronic renal failure (CRF) treatment. Our results demonstrated that AA caused rat renal failure and was tumorigenic by inducing the A:T→T:A transversion mutation at codon 61 of the H-ras gene thereby triggering oncogenic activity. The mutation incidence was heightened in the stomach tissue of rats with 5/6 CRF.
Section snippets
Chemicals
Aristolochic acid (AA) in the form of sodium salt was purchased from SIGMA (St Louis, MO, USA), and contained 58% AAI and 36% AAII.
Animal model
Eight-week-old wistar rats weighing ∼150±60 g were used in this study. Rats were divided into four groups as follows: group A (control group), normal rats (n=5) fed without AA; group B, normal rats (n=10) fed with AA; group C, 5/6 CRF (chronic renal failure) rats (n=10) fed without AA; and group D, 5/6 CRF rats (n=10) fed with AA. For the 5/6 CRF model (groups C and
Animal growth
We found that normal rats in group A without AA treatment gained considerably more weight than those in group B fed with AA (Fig. 1). 5/6 CRF treatment (group C) also reduced weight gain as shown in Fig. 1. The combination of 5/6 CRF treatment and AA supplement further slowed rat growth. In addition, the survival of animals was lower after administration of AA in 5/6 CRF-treated rats.
Serum creatinine
Elevated serum creatinine is generally considered as a major indicator for renal failure; therefore, both
Discussion
Aristolochic acids (AAs) have been detected in several commercially available Chinese herbal medicines [30] and are suspected to be associated with more than 200 cases of severe nephropathy or Chinese herb nephropathy (CHN) worldwide [4], [5], [7], [31], [32], [33]. The majority of CHN patients needed to undergo renal replacement therapy and some of them have developed cancer [4], [5], [31]. However, many other people who followed the same slimming regimen were not diagnosed with CHN [23]. Some
Acknowledgements
This work was supported by grants from Tunghai University, Taichung, ROC and Taichung Veterans General Hospital, Taichung, ROC to J.Y. Gu and C.L. Cheng.
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2021, Journal of Herbal MedicineCitation Excerpt :The adverse reaction induced by AAs is unnoticed because the symptoms need to be correlated precisely with the history of using products containing AAs or biochemical and pathological abnormalities of the kidney. AAs were identified as some of the main causative agents that induce rapidly progressive renal disease (Balachandran et al., 2005; Bloch et al., 2015; Bunel et al., 2015; Cheng et al., 2006; Hoang et al., 2016; Shaohua et al., 2010; Turesky et al., 2016). Both AA-I and AA-II are toxic to cultured cells, but later it was found that AA-I was the main compound that caused nephrotoxicity accompanied with AAN in mice (Han et al., 2019).
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2017, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :Nephrotoxic aristolochic acids (AAs) are a type of nitrophenanthrene carboxylic acids derivatives that root in Aristolochiaceae plants including Aristolochia and Asarum genera [1]. Most of the components have been revealed to be nephrotoxic [2–4], carcinogenic [5,6] and mutagenic [7,8]. Among them, AA-I, a major compound in AA-containing herbs, was found to be the most toxic and attracted the most attention [9].
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2013, Journal of EthnopharmacologyCitation Excerpt :However, aristolochic acid was more nephrotoxic than tetrandrine in mice, presenting elevated blood urea nitrogen and increased renal tubular injuries. Other rodent (Mengs, 1987; Debelle et al., 2003, 2002; Cheng et al., 2006;; Shibutani et al., 2007; Yeh et al., 2008) and rabbit studies (Cosyns et al., 2001; Chen et al., 2007) demonstrated the nephrotoxic effects of aristolochic acid. Interestingly, the results from Yeh et al. (2008) showed that aristolochic acid B (AA-B) induced kidney and liver dysfunction, while Shibutani et al. (2007) concluded that aristolochic acid A (AA-A) was solely responsible for the nephrotoxicity effects.
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