In vivo metabolism of aristolochic acid I and II in rats is influenced by their co-exposure

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F20%3A10414837" target="_blank" >RIV/00216208:11310/20:10414837 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/75010330:_____/20:00013346

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=1zW6zIk4Dt" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=1zW6zIk4Dt</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.chemrestox.0c00198" target="_blank" >10.1021/acs.chemrestox.0c00198</a>

Jazyk výsledku

angličtina

Název v původním jazyce

In vivo metabolism of aristolochic acid I and II in rats is influenced by their co-exposure

Popis výsledku v původním jazyce

The plant extract aristolochic acid (AA), containing aristolochic acid I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy and Balkan endemic nephropathy, unique renal diseases associated with upper urothelial cancer. Differences in the metabolic activation and detoxification of AAI and AAII and their effects on the metabolism of AAI/AAII mixture in the plant extract might be of great importance for an individual&apos;s susceptibility in the development of AA-mediated nephropathies and malignancies. Here, we investigated in vivo metabolism of AAI and AAII after i.p. administration to Wistar rats as individual compounds and as AAI/AAII mixture using high performance liquid chromatography/electrospray ionization mass spectrometry. Experimental findings were supported by theoretical calculations using density functional theory. We found that exposure to AAI/AAII mixture affected the generation of their oxidative and reductive metabolites formed during Phase I biotransformation and excreted in rat urine. Several Phase II metabolites of AAI and AAII found in the urine of exposed rats were also analysed. Our results indicate that AAI is more efficiently metabolised in rats in vivo than AAII. Whereas AAI is predominantly oxidised during in vivo metabolism, its reduction is the minor metabolic pathway. In contrast, AAII is mainly metabolised by reduction. The oxidative reaction only occurs if aristolactam II, the major reductive metabolite of AAII, is enzymatically hydroxylated, forming aristolactam Ia. In AAI/AAII mixture, the metabolism of AAI and AAII is influenced by the presence of both AAs. For instance, the reductive metabolism of AAI is increased in the presence of AAII while the presence of AAI decreased the reductive metabolism of AAII. These results suggest that increased bioactivation of AAI in the presence of AAII also leads to increased AAI genotoxicity which may critically impact on AAI-mediated carcinogenesis. Future studies are needed to explain the underlying mechanism(s) for this phenomenon.

Název v anglickém jazyce

In vivo metabolism of aristolochic acid I and II in rats is influenced by their co-exposure

Popis výsledku anglicky

The plant extract aristolochic acid (AA), containing aristolochic acid I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy and Balkan endemic nephropathy, unique renal diseases associated with upper urothelial cancer. Differences in the metabolic activation and detoxification of AAI and AAII and their effects on the metabolism of AAI/AAII mixture in the plant extract might be of great importance for an individual&apos;s susceptibility in the development of AA-mediated nephropathies and malignancies. Here, we investigated in vivo metabolism of AAI and AAII after i.p. administration to Wistar rats as individual compounds and as AAI/AAII mixture using high performance liquid chromatography/electrospray ionization mass spectrometry. Experimental findings were supported by theoretical calculations using density functional theory. We found that exposure to AAI/AAII mixture affected the generation of their oxidative and reductive metabolites formed during Phase I biotransformation and excreted in rat urine. Several Phase II metabolites of AAI and AAII found in the urine of exposed rats were also analysed. Our results indicate that AAI is more efficiently metabolised in rats in vivo than AAII. Whereas AAI is predominantly oxidised during in vivo metabolism, its reduction is the minor metabolic pathway. In contrast, AAII is mainly metabolised by reduction. The oxidative reaction only occurs if aristolactam II, the major reductive metabolite of AAII, is enzymatically hydroxylated, forming aristolactam Ia. In AAI/AAII mixture, the metabolism of AAI and AAII is influenced by the presence of both AAs. For instance, the reductive metabolism of AAI is increased in the presence of AAII while the presence of AAI decreased the reductive metabolism of AAII. These results suggest that increased bioactivation of AAI in the presence of AAII also leads to increased AAI genotoxicity which may critically impact on AAI-mediated carcinogenesis. Future studies are needed to explain the underlying mechanism(s) for this phenomenon.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA18-10251S" target="_blank" >GA18-10251S: Komplexní pohled na mechanismus působení a metabolismus inhibitorů tyrosinkinas a studium přístupů k potenciaci jejich protinádorové účinnosti</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Chemical Research in Toxicology

ISSN

0893-228X

e-ISSN

—

Svazek periodika

33

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

2804-2818

Kód UT WoS článku

000599310100012

EID výsledku v databázi Scopus

2-s2.0-85096202875