In vivo metabolism of aristolochic acid I and II in rats is influenced by their co-exposure
The result's identifiers
Result code in 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>
Alternative codes found
RIV/75010330:_____/20:00013346
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
In vivo metabolism of aristolochic acid I and II in rats is influenced by their co-exposure
Original language description
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'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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/GA18-10251S" target="_blank" >GA18-10251S: Comprehensive insight into mechanisms of action and metabolism of tyrosine kinase inhibitors and a study of ways increasing their antitumor efficiency</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Chemical Research in Toxicology
ISSN
0893-228X
e-ISSN
—
Volume of the periodical
33
Issue of the periodical within the volume
11
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
2804-2818
UT code for WoS article
000599310100012
EID of the result in the Scopus database
2-s2.0-85096202875