Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated.

• MeSH
• achondroplazie farmakoterapie   MeSH
• benzamidy farmakologie   MeSH
• chondrocyty metabolismus   MeSH
• chrupavka účinky léků   metabolismus   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• katalýza účinky léků   MeSH
• kultivované buňky MeSH
• kuřecí embryo MeSH
• lidé MeSH
• myši MeSH
• piperaziny farmakologie   MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• receptory fibroblastových růstových faktorů antagonisté a inhibitory   MeSH
• signální transdukce účinky léků   MeSH
• syndrom MeSH
• tyrosinkinasové receptory antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• cationic surfactants, micellar catalysis, decontamination, Resamin AE,
• MeSH
• chemické bojové látky škodlivé účinky   toxicita   MeSH
• dekontaminace metody   MeSH
• detergenty chemie   MeSH
• financování organizované MeSH
• hydrolýza účinky léků   MeSH
• katalýza účinky léků   MeSH
• klinické laboratorní techniky využití   MeSH
• lidé MeSH
• micely MeSH
• organofosforové sloučeniny metabolismus   škodlivé účinky   MeSH
• peroxid vodíku MeSH
• povrchově aktivní látky farmakokinetika   farmakologie   metabolismus   MeSH
• soman farmakokinetika   metabolismus   škodlivé účinky   MeSH
• teoretické modely MeSH
• Check Tag
• lidé MeSH

Silybin (a flavonolignan, the main component of silymarin, an extract from the seeds of Silybum marianum) has been used to date mostly as a hepatoprotectant. However, it also has other interesting activities, e.g., anticancer and hypocholesterolemic effects. It is also known that silybin can inhibit the activities of the cytochrome P450 (P450) enzymes. In this study, a weak interaction of silybin with human microsomal CYP2E1, 2A6, 2B6, 2C19, and 2D6 (IC(50) > or = 250 microM) was found; a moderate inhibition was observed for CYP1A2 and 2C8. The most prominent inhibition effect was found with CYP3A4 and CYP2C9 (IC(50) < or = 50 microM). Using mass spectometry detection, production of O-demethylated (the main metabolite) as well as hydroxylated derivatives of silybin formed by P450 enzymes was detected. The effect of different P450 inhibitors on the formation of O-demethylated product was also studied. In particular, a relatively specific inhibitor of CYP2C8 (quercetin) markedly inhibited the formation of this metabolite. With the help of recombinant enzymes (bactosomes), it was confirmed that the CYP2C8 enzyme is responsible for the reaction leading to O-demethylated silybin.

• MeSH
• antioxidancia farmakologie   metabolismus   MeSH
• aromatické hydroxylasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• cytochrom P-450 CYP3A MeSH
• Escherichia coli genetika   metabolismus   MeSH
• financování organizované MeSH
• inhibitory enzymů farmakologie   metabolismus   MeSH
• jaterní mikrozomy enzymologie   metabolismus   účinky léků   MeSH
• katalýza účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• oxid uhelnatý farmakologie   MeSH
• quercetin farmakologie   MeSH
• rekombinantní proteiny metabolismus   MeSH
• silymarin farmakologie   chemie   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 antagonisté a inhibitory   genetika   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH

Cellular signaling by glucocorticoid receptor and aryl hydrocarbon receptor is restricted by microtubules interfering agents (MIAs). This leads to down-regulation of drug metabolizing enzymes and drug interactions. Here we investigated the effects of all-trans-retinoic acid (ATRA) and MIAs, i.e. colchicine, nocodazole and taxol on the regulation of retinoic acid receptor (RAR) genes in primary cultures of rat hepatocytes. ATRA (1microM) down-regulated RARalpha and RARgamma mRNAs (decrease 23% and 41%, respectively) whereas it up-regulated RARbeta mRNA (4.3-fold induction). All MIAs diminished the expression of RARs in dose-dependent manner; the potency of MIAs increased in order NOC

• MeSH
• financování organizované MeSH
• genetická transkripce účinky záření   MeSH
• HeLa buňky cytologie   metabolismus   účinky léků   MeSH
• katalýza účinky léků   MeSH
• kolchicin farmakologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• leupeptiny farmakologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mikrotubuly účinky léků   MeSH
• modulátory tubulinu farmakologie   MeSH
• proteasomový endopeptidasový komplex antagonisté a inhibitory   MeSH
• receptory kyseliny retinové genetika   metabolismus   MeSH
• regulace genové exprese účinky záření   MeSH
• termodynamika MeSH
• transglutaminasy metabolismus   MeSH
• tretinoin farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH