International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

• MeSH
• genom lidský genetika   MeSH
• genomika MeSH
• hypertenze epidemiologie   MeSH
• incidence MeSH
• karcinom z renálních buněk * genetika   epidemiologie   chemicky indukované   MeSH
• kouření tabáku škodlivé účinky   genetika   MeSH
• kyseliny aristolochové škodlivé účinky   MeSH
• lidé MeSH
• mutace * MeSH
• mutageny * škodlivé účinky   MeSH
• nádory ledvin * genetika   epidemiologie   chemicky indukované   MeSH
• obezita epidemiologie   MeSH
• rizikové faktory MeSH
• vystavení vlivu životního prostředí * škodlivé účinky   analýza   MeSH
• zeměpis * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Japonsko epidemiologie   MeSH
• Rumunsko epidemiologie   MeSH
• Srbsko epidemiologie   MeSH
• Thajsko epidemiologie   MeSH
• Názvy látek
• kyseliny aristolochové MeSH
• mutageny * MeSH

Aristolochic acids (AAs) are a group of naturally occurring compounds present in many plant species of the Aristolochiaceae family. Exposure to AA is a significant risk factor for severe nephropathy, and urological and hepatobiliary cancers (among others) that are often recurrent and characterized by the prominent mutational fingerprint of AA. However, herbal medicinal products that contain AA continue to be manufactured and marketed worldwide with inadequate regulation, and possible environmental exposure routes receive little attention. As the trade of food and dietary supplements becomes increasingly globalized, we propose that further inaction on curtailing AA exposure will have far-reaching negative effects on the disease trends of AA-associated cancers. Our Review aims to systematically present the historical and current evidence for the mutagenicity and carcinogenicity of AA, and the effect of removing sources of AA exposure on cancer incidence trends. We discuss the persisting challenges of assessing the scale of AA-related carcinogenicity, and the obstacles that must be overcome in curbing AA exposure and preventing associated cancers. Overall, this Review aims to strengthen the case for the implementation of prevention measures against AA's multifaceted, detrimental and potentially fully preventable effects on human cancer development.

• MeSH
• kyseliny aristolochové * toxicita   MeSH
• lidé MeSH
• mutageneze MeSH
• nádory * chemicky indukované   epidemiologie   MeSH
• veřejné zdravotnictví MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• aristolochic acid I MeSH Prohlížeč
• kyseliny aristolochové * MeSH

The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804-2818, 2020), we showed that the in vivo metabolism of AAI and AAII in Wistar rats is influenced by their co-exposure (i.e., AAI/AAII mixture). Using the same rat model, we investigated how exposure to the AAI/AAII mixture can influence AAI and AAII DNA adduct formation (i.e., AA-mediated genotoxicity). Using 32P-postlabelling, we found that AA-DNA adduct formation was increased in the livers and kidneys of rats treated with AAI/AAII mixture compared to rats treated with AAI or AAII alone. Measuring the activity of enzymes involved in AA metabolism, we showed that enhanced AA-DNA adduct formation might be caused partially by both decreased AAI detoxification as a result of hepatic CYP2C11 inhibition during treatment with AAI/AAII mixture and by hepatic or renal NQO1 induction, the key enzyme predominantly activating AA to DNA adducts. Moreover, our results indicate that AAII might act as an inhibitor of AAI detoxification in vivo. Consequently, higher amounts of AAI might remain in liver and kidney tissues, which can be reductively activated, resulting in enhanced AAI DNA adduct formation. Collectively, these results indicate that AAII present in the plant extract AA enhances the genotoxic properties of AAI (i.e., AAI DNA adduct formation). As patients suffering from AAN and BEN are always exposed to the plant extract (i.e., AAI/AAII mixture), our findings are crucial to better understanding host factors critical for AAN- and BEN-associated urothelial malignancy.

• Klíčová slova
• Balkan endemic nephropathy, DNA adducts, NAD(P)H:quinone oxidoreductase 1, aristolochic acid I, aristolochic acid II, aristolochic acid nephropathy, aristolochic acid-mediated carcinogenesis, cytochrome P450, genotoxicity,
• MeSH
• adukty DNA metabolismus   MeSH
• DNA nádorová metabolismus   MeSH
• karcinogeneze * chemicky indukované   metabolismus   MeSH
• karcinogeny toxicita   MeSH
• krysa rodu Rattus MeSH
• kyseliny aristolochové toxicita   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adukty DNA MeSH
• aristolochic acid B MeSH Prohlížeč
• aristolochic acid I MeSH Prohlížeč
• DNA nádorová MeSH
• karcinogeny MeSH
• kyseliny aristolochové MeSH

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (P = 10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single RAS/MAPK driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers.This article is highlighted in the In This Issue feature, p. 1307.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• celosvětové zdraví MeSH
• dítě MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• gliom farmakoterapie   genetika   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   genetika   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy kinas genetika   MeSH
• mutace MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory mozku farmakoterapie   genetika   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antitumorózní látky MeSH
• inhibitory proteinkinas MeSH
• mitogenem aktivované proteinkinasy kinas MeSH

Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(-/-) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography-mass spectrometry (GC-MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice and exposed them to AAI in vitro (50 µM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(-/-) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(-/-) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

• Klíčová slova
• Aristolochic acid I, Carcinogen metabolism, DNA adducts, Mouse embryonic fibroblasts, Mouse models, Tumour suppressor p53,
• MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• exprese genu účinky léků   MeSH
• fibroblasty účinky léků   metabolismus   patologie   MeSH
• kultivované buňky MeSH
• kyseliny aristolochové metabolismus   toxicita   MeSH
• mutageny metabolismus   toxicita   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• NAD(P)H dehydrogenasa (chinon) genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• poškození DNA * MeSH
• proximální tubuly ledvin účinky léků   metabolismus   patologie   MeSH
• vyšetření funkce ledvin MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aristolochic acid I MeSH Prohlížeč
• Cyp1a1 protein, mouse MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• kyseliny aristolochové MeSH
• mutageny MeSH
• NAD(P)H dehydrogenasa (chinon) MeSH
• nádorový supresorový protein p53 MeSH
• Nqo1 protein, mouse MeSH Prohlížeč
• Trp53 protein, mouse MeSH Prohlížeč

The information on candidate cancer driver alterations available from public databases is often descriptive and of limited mechanistic insight, which poses difficulties for reliable distinction between true driver and passenger events. To address this challenge, we performed in-depth analysis of whole-exome sequencing data from cell lines generated by a barrier bypass-clonal expansion (BBCE) protocol. The employed strategy is based on carcinogen-driven immortalization of primary mouse embryonic fibroblasts and recapitulates early steps of cell transformation. Among the mutated genes were almost 200 COSMIC Cancer Gene Census genes, many of which were recurrently affected in the set of 25 immortalized cell lines. The alterations affected pathways regulating DNA damage response and repair, transcription and chromatin structure, cell cycle and cell death, as well as developmental pathways. The functional impact of the mutations was strongly supported by the manifestation of several known cancer hotspot mutations among the identified alterations. We identified a new set of genes encoding subunits of the BAF chromatin remodeling complex that exhibited Ras-mediated dependence on PRC2 histone methyltransferase activity, a finding that is similar to what has been observed for other BAF subunits in cancer cells. Among the affected BAF complex subunits, we determined Smarcd2 and Smarcc1 as putative driver candidates not yet fully identified by large-scale cancer genome sequencing projects. In addition, Ep400 displayed characteristics of a driver gene in that it showed a mutually exclusive mutation pattern when compared with mutations in the Trrap subunit of the TIP60 complex, both in the cell line panel and in a human tumor data set. We propose that the information generated by deep sequencing of the BBCE cell lines coupled with phenotypic analysis of the mutant cells can yield mechanistic insights into driver events relevant to human cancer development.

• MeSH
• exom genetika   MeSH
• fibroblasty MeSH
• lidé MeSH
• mutace MeSH
• myši MeSH
• nádorová transformace buněk genetika   MeSH
• nádorové proteiny genetika   MeSH
• nádory genetika   MeSH
• primární buněčná kultura MeSH
• vysoce účinné nukleotidové sekvenování * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• nádorové proteiny MeSH

Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading to specific A:T to T:A transversion mutations (mutational signature) in AAN/BEN-associated tumours, which are otherwise rare in individuals with UCC not exposed to AA. Therefore, such DNA damage produced by AA-DNA adducts is one rare example of the direct association of exposure and cancer development (UUC) in humans, confirming that the covalent binding of carcinogens to DNA is causally related to tumourigenesis. Although aristolochic acid I (AAI), the major component of the natural plant extract AA, might directly cause interstitial nephropathy, enzymatic activation of AAI to reactive intermediates capable of binding to DNA is a necessary step leading to the formation of AA-DNA adducts and subsequently AA-induced malignant transformation. Therefore, AA-DNA adducts can not only be utilized as biomarkers for the assessment of AA exposure and markers of AA-induced UUC, but also be used for the mechanistic evaluation of its enzymatic activation and detoxification. Differences in AA metabolism might be one of the reasons for an individual's susceptibility in the multi-step process of AA carcinogenesis and studying associations between activities and/or polymorphisms of the enzymes metabolising AA is an important determinant to identify individuals having a high risk of developing AA-mediated UUC.

• Klíčová slova
• DNA adduct formation, aristolochic acid, carcinogenicity, mutagenesis, nephrotoxicity,
• MeSH
• adukty DNA metabolismus   MeSH
• balkánská nefropatie etiologie   metabolismus   MeSH
• biologické markery * MeSH
• karcinogeny chemie   metabolismus   MeSH
• kyseliny aristolochové chemie   metabolismus   MeSH
• lidé MeSH
• náchylnost k nemoci MeSH
• nádorová transformace buněk genetika   metabolismus   MeSH
• urologické nádory etiologie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adukty DNA MeSH
• biologické markery * MeSH
• karcinogeny MeSH
• kyseliny aristolochové MeSH

Exposure to aristolochic acid (AA) causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Conflicting results have been found for the role of human sulfotransferase 1A1 (SULT1A1) contributing to the metabolic activation of aristolochic acid I (AAI) in vitro. We evaluated the role of human SULT1A1 in AA bioactivation in vivo after treatment of transgenic mice carrying a functional human SULT1A1-SULT1A2 gene cluster (i.e. hSULT1A1/2 mice) and Sult1a1(-/-) mice with AAI and aristolochic acid II (AAII). Both compounds formed characteristic DNA adducts in the intact mouse and in cytosolic incubations in vitro. However, we did not find differences in AAI-/AAII-DNA adduct levels between hSULT1A1/2 and wild-type (WT) mice in all tissues analysed including kidney and liver despite strong enhancement of sulfotransferase activity in both kidney and liver of hSULT1A1/2 mice relative to WT, kidney and liver being major organs involved in AA metabolism. In contrast, DNA adduct formation was strongly increased in hSULT1A1/2 mice compared to WT after treatment with 3-nitrobenzanthrone (3-NBA), another carcinogenic aromatic nitro compound where human SULT1A1/2 is known to contribute to genotoxicity. We found no differences in AAI-/AAII-DNA adduct formation in Sult1a1(-/-) and WT mice in vivo. Using renal and hepatic cytosolic fractions of hSULT1A1/2, Sult1a1(-/-) and WT mice, we investigated AAI-DNA adduct formation in vitro but failed to find a contribution of human SULT1A1/2 or murine Sult1a1 to AAI bioactivation. Our results indicate that sulfo-conjugation catalysed by human SULT1A1 does not play a role in the activation pathways of AAI and AAII in vivo, but is important in 3-NBA bioactivation.

• Klíčová slova
• 3-Nitrobenzanthrone, Aristolochic acid nephropathy, Balkan endemic nephropathy, Carcinogen metabolism, DNA adducts, Sulfotransferase 1A1,
• MeSH
• adukty DNA účinky léků   genetika   MeSH
• arylsulfotransferasa genetika   MeSH
• benz(a)anthraceny toxicita   MeSH
• cytosol účinky léků   metabolismus   MeSH
• játra účinky léků   metabolismus   MeSH
• karcinogeny toxicita   MeSH
• kyseliny aristolochové toxicita   MeSH
• ledviny účinky léků   metabolismus   MeSH
• lidé MeSH
• multigenová rodina MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-nitrobenzanthrone MeSH Prohlížeč
• adukty DNA MeSH
• arylsulfotransferasa MeSH
• benz(a)anthraceny MeSH
• karcinogeny MeSH
• kyseliny aristolochové MeSH
• SULT1A1 protein, human MeSH Prohlížeč
• SULT1A2 protein, human MeSH Prohlížeč

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.

• Klíčová slova
• Aristolochic acid, Aristolochic acid nephropathy, Balkan endemic nephropathy, Disease aetiology, Environmental and genetic factors, Upper urothelial cancer,
• MeSH
• Aristolochia chemie   růst a vývoj   toxicita   MeSH
• balkánská nefropatie chemicky indukované   epidemiologie   patofyziologie   prevence a kontrola   MeSH
• dieta škodlivé účinky   MeSH
• endemické nemoci * MeSH
• faktory vyvracející (epidemiologie) MeSH
• karcinogeny životního prostředí analýza   toxicita   MeSH
• kontaminace potravin * prevence a kontrola   MeSH
• kyseliny aristolochové analýza   toxicita   MeSH
• ledviny účinky léků   patofyziologie   MeSH
• léková rezistence MeSH
• lidé MeSH
• medicína založená na důkazech * MeSH
• mouka škodlivé účinky   analýza   MeSH
• plevel chemie   růst a vývoj   toxicita   MeSH
• prevalence MeSH
• pšenice růst a vývoj   MeSH
• riziko MeSH
• semena rostlinná růst a vývoj   MeSH
• urologické nádory chemicky indukované   epidemiologie   patofyziologie   prevence a kontrola   MeSH
• zemědělské plodiny růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• východní Evropa epidemiologie   MeSH
• Názvy látek
• aristolochic acid I MeSH Prohlížeč
• karcinogeny životního prostředí MeSH
• kyseliny aristolochové MeSH

UNLABELLED: Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H: quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the (32)P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts.

• Klíčová slova
• Aristolochic acid I, Cytochromes P450 1A1 and 1A2, DNA adducts, Oxidative detoxification, Reductive activation,
• MeSH
• adukty DNA antagonisté a inhibitory   biosyntéza   MeSH
• cytochrom P-450 CYP1A1 biosyntéza   MeSH
• cytochrom P-450 CYP1A2 biosyntéza   MeSH
• enzymová indukce účinky léků   fyziologie   MeSH
• karcinogeny toxicita   MeSH
• krysa rodu Rattus MeSH
• kyseliny aristolochové toxicita   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• aristolochic acid I MeSH Prohlížeč
• CYP1A1 protein, human MeSH Prohlížeč
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• karcinogeny MeSH
• kyseliny aristolochové MeSH