Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells

Balachandran, Premalatha; Wei, Feng; Lin, Rui‐Chao; Khan, Ikhlas A.; Pasco, David S.

doi:10.1111/j.1523-1755.2005.00277.x

Cited by 159 publications

(139 citation statements)

References 50 publications

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“…45 Furthermore, aristolochic acid isolated from Aristolochia fangchi was shown to induce cellular injury and apoptosis in proximal tubular (LLC-PK1) epithelial cell lines. [46][47][48][49] The results described in this study introduce the first in vivo evidence that the previously reported OA-evoked increases in urinary Na þ output are in part mediated via inhibition of Na þ reabsorption and increases in proximal tubular Na þ secretion. The study provides the first in vitro evidence that OA does not exhibit toxicity in kidney and liver cell lines and implicates the proximal tubule in the natriuretic effects of OA.…”

supporting

confidence: 66%

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

et al. 2012

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Studies indicate that Syzygium spp-derived oleanolic acid (OA) enhances renal function of streptozotocin (STZ)-induced diabetic rats as evidenced by its reversal of the previously reported inability of the kidney to excrete Na þ in these animals. We postulated that OA influences Na þ excretion in the proximal tubule, the site where two-thirds of filtered NaCl is reabsorbed through a process mediated by transport proteins. Therefore, the study investigated the effects of OA on proximal tubular Na þ handling in male Sprague-Dawley rats using renal lithium clearance (C Li ). Renal C Li has been used widely in animal and clinical studies to assess proximal tubular function. Sub-chronic doses of OA were administered to rats twice every third day for 5 weeks. Rats treated with deionized water served as control animals. Cytotoxicity of OA on kidney and liver cell lines was assessed by the MTT and comet assays. OA increased Na þ excretion of conscious male Sprague-Dawley rats from week 3 to week 5. By the end of the 5-week experimental period, OA treatment significantly reduced (p < 0.05) plasma creatinine concentration of STZ-induced diabetic rats with a concomitant elevation in glomerular filtration rate (GFR). Acute OA infusion was also associated with increases in fractional excretion of sodium (FE Na ) and lithium (FE Li ) in anesthetized rats in the absence of significant changes in GFR. The MTT assay studies demonstrated that OA increased the metabolic activity of kidney and liver cell lines. Taken together with previous observations, this study implicates the proximal tubule in OA-evoked increases in urinary Na þ output.

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confidence: 66%

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

et al. 2012

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“…In the roots, AA-IVa (7) Because AA-I (1) and AA-II(2) can be easily obtained commercially and are much more widely distributed in Aristolochia, 2 studies of the toxicity and mechanisms of action of AAs have been mostly restricted to those compounds. [5][6][7][8][9][10] An exception is a study of the toxicity of several AA derivatives in cultured rat renal epithelial cells, 7 in which AA-I (1), AA-II (2), AA-VIIIa, and AA-Ia (5) were shown to have nearly identical levels of activity, while other AA derivatives, AA-III (3), AA-IIIa (6), AA-IVa (7), AA-VIa, and 7-hydroxy-AA-I, were nearly inactive. These results indicate a direct relationship between the activity and localization of the substituents in the structure of the AAs.…”

Section: Results and Discusionmentioning

confidence: 99%

“…Studies have shown that these AAs are genotoxic, mutagenic, and nephrotoxic. [5][6][7][8][9][10] The mechanism underlying the toxicity of AAs AA-I (1) and AA-II (2) involves a reduction of the nitro group (which is catalyzed by an enzyme) to the very reactive cyclic nitrenium ion, which then binds covalently to DNA and/or proteins. DNA adducts with the reduction products of AAs have been found in the kidney and ureter tissues of rats and humans that had consumed AAs.…”

Section: Introductionmentioning

confidence: 99%

Aristolochic Acids in the Roots of Aristolochia Chilensis, a Dangerous Chilean Medicinal Plant

Urzúa

Olguín

Santander

2013

J. Chil. Chem. Soc.

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“…The pathology is characterized by tubulointerstitial disease and fibrosis. Although the mechanism is not certain, these substances are clearly toxic to cultured renal epithelial cells (55). There is also a high incidence of uroepithelial cancer in these patients.…”

Section: Drugs and Toxinsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

215

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells

Abstract: These cytotoxic data suggest that the nitro and methoxy groups are critical determinants of nephrotoxicologic potency of AA.

Cited by 159 publications

References 50 publications

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

Aristolochic Acids in the Roots of Aristolochia Chilensis, a Dangerous Chilean Medicinal Plant

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

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