Abstract
Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been used for decades to treat various diseases. However, the consumption of products derived from plants containing AA has been associated with the development of nephropathy and carcinoma, mainly the upper urothelial carcinoma (UUC). AA has been identified as the causative agent of these pathologies. Several studies on mechanisms of action of AA nephrotoxicity have been conducted, but the comprehensive mechanisms of AA-induced nephrotoxicity and carcinogenesis have not yet fully been elucidated, and therapeutic measures are therefore limited. This review aimed to summarize the molecular mechanisms underlying AA-induced nephrotoxicity with an emphasis on its enzymatic bioactivation, and to discuss some agents and their modes of action to reduce AA nephrotoxicity. By addressing these two aspects, including mechanisms of action of AA nephrotoxicity and protective approaches against the latter, and especially by covering the whole range of these protective agents, this review provides an overview on AA nephrotoxicity. It also reports new knowledge on mechanisms of AA-mediated nephrotoxicity recently published in the literature and provides suggestions for future studies.
Highlights
Remedies prepared from Aristolochiaceae plants containing aristolochic acid (AA) under various pharmaceutical formulations, including pills, powder, granules, pellets, infusions, and capsules [1,2], have been used for decades throughout the world to treat diverse diseases, including hepatitis, urinary tract infection, vaginitis, upper respiratory tract infection, eczema, dysmenorrhea, arthralgia, hypertension, bronchitis, pneumonia, heart failure, and edema [3,4,5]
A study by Chang and colleagues, using microphysiological systems, demonstrated that sulfotransferases (SULTs) were involved in enhancement of AA nephrotoxicity. They showed that, after nitroreduction of AAI mediated by NQO1 into aristolactam I (AL-I), the latter was converted into aristolactam-N-sulfate (AL-NOSO3H), a toxic metabolite that was transported out of the liver via multidrug resistance-associated protein (MRP) transporters, and taken into the kidney via organic anion transporters (OATs), and formed high DNA adducts levels [37]
A study by Zhou et al [59] reported that AA induced apoptosis in tubular epithelial cells (TECs) through dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and activation of p53 signaling pathways, and that in p53-deficient mice treated with AA, it resulted in massive apoptotic and necrotic TECs death
Summary
Remedies prepared from Aristolochiaceae plants containing aristolochic acid (AA) under various pharmaceutical formulations, including pills, powder, granules, pellets, infusions, and capsules [1,2], have been used for decades throughout the world to treat diverse diseases, including hepatitis, urinary tract infection, vaginitis, upper respiratory tract infection, eczema, dysmenorrhea, arthralgia, hypertension, bronchitis, pneumonia, heart failure, and edema [3,4,5]. A study by Chang and colleagues, using microphysiological systems (organs-on-chips), demonstrated that sulfotransferases (SULTs) were involved in enhancement of AA nephrotoxicity They showed that, after nitroreduction of AAI mediated by NQO1 into aristolactam I (AL-I), the latter was converted into aristolactam-N-sulfate (AL-NOSO3H), a toxic metabolite that was transported out of the liver via multidrug resistance-associated protein (MRP) transporters, and taken into the kidney via organic anion transporters (OATs), and formed high DNA adducts levels [37]. AA is enzymatically reduced to reactive intermediates that generate DNA adducts, of which dA-AAI constitutes the dominant and most persistent AA-DNA adducts These adducts can accumulate in target organs such as the renal cortex, serving as biomarkers of prior to long-term exposure to AA or cause Tp53 mutations (Figure 2) in some tissues, such as the upper urinary track [43]. P. roPpropseodsemdemtaebtoalbioclpicatphawthawy aoyf AoAf AI aAnIdaAnAdIAI wAhIIicwhhleicahdsletoadths etior athcteiivraaticotinv.aAtiAonI.aAndAAI AanIdI aAreAIrIedaruecereddubcyedNbAyDN(PA)HD:(Pq)Hui:nqounienoonxeidooxrieddourecdtausceta1se(N1 Q(NOQ1O), 1a),nadndcyctyotcohcrhormome ePP45405011AA11/1/1AA22 ((CCYYPP11AA11//2) iinnttooNN--hhyyddrrooxxyaristolacttaammss,, which can further bind ttooDDNNAAtotofoforrmmAAAA-D-DNNAAadaddduuctcsts, , iinncclluudding7-((ddeeooxxyyaaddeennoosisni-nN-N6-6y-ly) al)ristaorliascttoalmacItanmd III(dAan-AdAIIaInd(dA--AAAAII), aanndd7-(deAo-xAyAguIaI)n,osainn-dN2-7y-l) (adreisotxoylagcutaamnoIsain-dNI2I -(ydlG) -aArAistIoalnadctdamG-IAaAnIdI).INI (-hdyGd-rAoAxyIaarinstdoldacGta-mAsAcIaIn).aNlso-hryedacrtowxyitahrissutolfloatcrtaanmsfsercaasens a(lSsUoLrTesa)cttowfoirtmh sNu-lsfoutlrfoaxnysaferirsatsoelasc(tSamUL, wTsh)ictho cfaonrmbeNtr-asnuslffoorxmyeadrisintotolaacrtiasmtol,awcthamichnictarennibuemtriaonnssf?o(rTmheedre iinstsotilal raismtoaltatecrtaomf denbiatrtenoinumthe icoonnsv?er(sTiohneoref Nis-susltfiollxyaarimstaotlatecrtamofindtoebaartisetoolanctatmhenictorennviuermsioionnso, hf eNnc-e stuhlefoqxuyeasrtiostnomlaactrakminiFnitgouraeri2s.t)oTlahcetsaemDNniAtreandiduumctsiolenasd, thoetnucme otrhesuqpuperesstisoonr Tmp5a3rkgeinefmigutraetio2.n)s.These DNA adducts lead to tumor suppressor Tp53 gene mutations
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