Estrogeny jsou klíčové hormony, které hrají zásadní roli ve fyziologii reprodukčního systému u žen. Jejich terapeutické využití v hormonální léčbě, antikoncepci a léčbě hormonálně závislých onemocnění však může být spojeno s řadou nežádoucích účinků, zejména na játra. Tento článek se zaměřuje na mechanizmy působení estrogenů a jejich potenciální hepatotoxické účinky, stejně jako na rizikové faktory a možné rozdíly mezi jednotlivými představiteli.
Estrogens are key hormones that play a vital role in the physiology of the reproductive system in women. However, their therapeutic use in hormonal treatment, contraception, and the treatment of hormone-dependent diseases may be associated with a number of side effects, especially on the liver. This article focuses on the mechanisms of action of estrogens and their potential hepatotoxic effects, as well as risk factors and possible differences between representatives.
- MeSH
- estetrol farmakologie metabolismus škodlivé účinky MeSH
- estradiol farmakologie metabolismus škodlivé účinky MeSH
- estrogeny * farmakologie metabolismus škodlivé účinky MeSH
- ethinylestradiol farmakologie metabolismus škodlivé účinky MeSH
- játra * metabolismus patologie účinky léků MeSH
- lékové interakce fyziologie MeSH
- lékové postižení jater etiologie metabolismus MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
OBJECTIVES: 17α-Ethinylestradiol (EE2) is an endocrine disruptor that is an ingredient of oral contraceptives. Here, EE2 metabolism catalyzed by cytochromes P450 (CYP) was studied. Two model organisms, rat and ligninolytic fungus Pleurotus ostreatus, were used. METHODS: To resolve the role of rat and/or fungal CYPs in EE2 oxidation, microsomes were incubated with EE2 and NADPH or cumene hydroperoxide. Using Supersomes™, we examined which of rat CYPs oxidize EE2. RESULTS: EE2 is effectively degraded by P. ostreatus in vivo. In vitro, EE2 is metabolized by CYPs by the NADPH-dependent and organic hydroperoxide-dependent mechanisms. Rat hepatic microsomes metabolize EE2 in the presence of NADPH to three products; two of them are hydroxylated EE2 derivatives. Using rat Supersomes™ we found that EE2 is hydroxylated by several rat CYPs, among them CYP2C6 and 2C11 are most efficient in 2-hydroxy-EE2 formation, while CYP2A and 3A catalyze EE2 hydroxylation to the second product. On the contrary, the products of the NADPH-dependent hydroxylating reactions were not detected in Pleurotus ostreatus. During the reaction of EE2 in microsomes isolated from rat and P. ostreatus in the presence of the alternate oxidant, cumene hydroperoxide, another metabolite, different from the above mentioned products, is generated. Rat CYP1A1 is the most efficient enzyme catalyzing formation of this EE2 product. CONCLUSION: The results suggest that CYPs play a role in EE2 metabolism in rat and P. ostreatus. To our knowledge this is the first finding describing ligninolythic fungal metabolism of EE2 by CYP in the presence of cumene hydroperoxide.
- MeSH
- aromatické hydroxylasy metabolismus MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- ethinylestradiol metabolismus MeSH
- hydroxylace MeSH
- jaterní mikrozomy enzymologie metabolismus MeSH
- krysa rodu rattus MeSH
- oxidace-redukce MeSH
- Pleurotus MeSH
- potkani Wistar MeSH
- steroid-16-alfa-hydroxylasa metabolismus MeSH
- steroid-21-hydroxylasa metabolismus MeSH
- steroidhydroxylasy metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
17α-Ethinylestradiol (EE2) is an endocrine disruptor (ED) used as an ingredient of oral contraceptives. Rat hepatic microsomes metabolize EE2 to three products; two of them are hydroxylated EE2 derivatives. Of the hydroxylation reactions, 2-hydroxylation, is the major reaction. Cytochrome P450 (CYP) plays a major role in EE2 hydroxylation. To resolve which rat CYPs are responsible for EE2 oxidation, three approaches were used: induction of specific CYPs, selective inhibition of CYPs, and recombinant rat CYPs. The results demonstrate that EE2 is hydroxylated by several rat CYPs, among them CYP2C6 and 2C11 are most efficient in 2-hydroxy-EE2 formation, while CYP2A and 3A catalyze EE2 hydroxylation to the second product. EE2 is also an inhibitor of CYP2C- and CYP3A-catalyzed hydroxylation of endogenous EDs progesterone and testosterone. EE2 acts as a reversible inhibitor of CYP3A-mediated progesterone 6β-hydroxylation and inactivates CYP3A- and CYP2C-catalyzed testosterone 6β-hydroxylation and progesterone 21- or 16α-hydroxylation, respectively, in a mechanism-based manner.
- MeSH
- ethinylestradiol metabolismus MeSH
- hydroxylace MeSH
- jaterní mikrozomy metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- progesteron metabolismus MeSH
- rekombinantní proteiny metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- testosteron metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Užívání hormonální antikoncepce je považováno za rizikový faktor vzniku hluboké žilní trombózy a plicní embolie. Od zavedení hormonální antikoncepce v 60. letech 20. století byl u jejích uživatelek pozorován častější výskyt těchto komplikací. Nejnovější studie pak ukázaly dvakrát vyšší riziko vzniku žilní trombózy při užívání kombinovaných preparátů obsahujících progestiny třetí generace (desogestrel, gestoden, norgestimate) ve srovnávání s progestiny druhé generace (levonorgestrel a norgestrel), ačkoli progestiny třetí generace neprokázaly žádný klinicky významný benefit. Přičemž riziko vzniku hluboké žilní trombózy je ještě vyšší u neperorálních forem hormonální antikoncepce (vaginální kroužek, transdermální náplast).
Since the early 1960s, it has been well documented that combined hormonal contraceptives increase the risk of venous thrombosis. Second and third generation oral contraceptives (OCs) differ in their progestin component. Third generation OCs contain desogestrel, gestodene or norgestimate while second generation OCs contain norgestrel or levonorgestrel. In spite of the fact that the third generation OCs have not shown any clinically significant benefit over the second generation OC, multiple studies and two meta‑analyses show that the third generation OC containing desogestrel are associated with approximately doubled risk of venous thrombosis. The newer generation of oral formulations, as well as non‑oral contraceptives (transdermal and vaginal), were recently studied for thrombotic risk. In the context of contraceptives use, the non‑oral route of ethinyl‑estradiol administration seems to be more thrombogenic than the oral route.
- Klíčová slova
- NuvaRing,
- MeSH
- antikoncepční prostředky ženské * škodlivé účinky MeSH
- desogestrel analogy a deriváty farmakokinetika metabolismus škodlivé účinky MeSH
- ethinylestradiol farmakokinetika metabolismus škodlivé účinky MeSH
- fixní kombinace léků MeSH
- kombinace léků ethinylestradiol a norgestrel škodlivé účinky MeSH
- kontraceptiva orální hormonální škodlivé účinky MeSH
- kontraceptiva orální kombinovaná škodlivé účinky MeSH
- lidé MeSH
- mladý dospělý MeSH
- plicní embolie * diagnóza farmakoterapie chemicky indukované MeSH
- žilní trombóza * diagnóza farmakoterapie chemicky indukované MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
Fungal, ligninolytic enzymes have attracted a great attention for their bioremediation capabilities. A deficient knowledge of regulation of enzyme production, however, hinders the use of ligninolytic fungi in bioremediation applications. In this work, a transcriptional analyses of laccase and manganese peroxidase (MnP) production by two white rots was combined with determination of pI of the enzymes and the evaluation of 17α-ethinyloestradiol (EE2) degradation to study regulation mechanisms used by fungi during EE2 degradation. In the cultures of Trametes versicolor the addition of EE2 caused an increase in laccase activity with a maximum of 34.2 ± 6.7 U g⁻¹ of dry mycelia that was observed after 2 days of cultivation. It corresponded to a 4.9 times higher transcription levels of a laccase-encoding gene (lacB) that were detected in the cultures at the same time. Simultaneously, pI values of the fungal laccases were altered in response to the EE2 treatment. Like T. versicolor, Irpex lacteus was also able to remove 10 mg l⁻¹ EE2 within 3 days of cultivation. While an increase to I. lacteus MnP activity and MnP gene transcription levels was observed at the later phase of the cultivation. It suggests another metabolic role of MnP but EE2 degradation.
- MeSH
- ethinylestradiol metabolismus MeSH
- fungální proteiny genetika metabolismus MeSH
- kultivační média MeSH
- lakasa genetika metabolismus MeSH
- lignin metabolismus MeSH
- mycelium metabolismus MeSH
- peroxidasy genetika metabolismus MeSH
- Polyporales enzymologie genetika růst a vývoj MeSH
- průmyslová mikrobiologie metody MeSH
- regulace genové exprese enzymů * MeSH
- regulace genové exprese u hub MeSH
- Trametes enzymologie genetika růst a vývoj MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Natural estrogens such as estrone, 17beta-estradiol, estriol, and the particularly recalcitrant synthetic estrogen 17alpha-ethinylestradiol used as oral contraceptive, accumulate in the environment and may give rise to health problems. The processes participating in their removal from soil, wastewater, water-sediments, groundwater-aquifer material, and wastewater or sewage treatment plant effluents may involve the action of bacterial and microbial consortia, and in some cases fungi and algae. This review discusses the different efficiencies of bacterial degradation of 17alpha-ethinylestradiol under aerobic and anaerobic conditions, the role of sulfate-, nitrate-, and iron-reducing conditions in anaerobic degradation, and the role of sorption. The participation of autotrophic ammonia oxidizing bacteria and heterotrophic bacteria in cometabolic degradation of estrogens, the estrogen-degrading action of ligninolytic fungi and their extracellular enzymes (lignin peroxidase, manganese-dependent peroxidase, versatile peroxidase, laccase), and of algae are discussed in detail.
- MeSH
- Bacteria metabolismus MeSH
- biodegradace MeSH
- biotransformace MeSH
- estrogeny chemická syntéza metabolismus MeSH
- ethinylestradiol chemická syntéza metabolismus MeSH
- houby metabolismus MeSH
- látky znečišťující životní prostředí metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Endocrine-disrupting compounds (EDCs) represent a large group of substances of natural and anthropogenic origin. They are widely distributed in the environment and can pose serious risks to aquatic organisms and to public health. In this study, 4-n-nonylphenol, technical 4-nonylphenol, bisphenol A, 17alpha-ethinylestradiol, and triclosan were biodegraded by eight ligninolytic fungal strains (Irpex lacteus 617/93, Bjerkandera adusta 606/93, Phanerochaete chrysosporium ME 446, Phanerochaete magnoliae CCBAS 134/I, Pleurotus ostreatus 3004 CCBAS 278, Trametes versicolor 167/93, Pycnoporus cinnabarinus CCBAS 595, Dichomitus squalens CCBAS 750). The results show that under the used conditions the fungi were able to degrade the EDCs within 14d of cultivation with exception of B. adusta and P. chrysosporium in the case of triclosane and bisphenol A, respectively. I. lacteus and P. ostreatus were found to be most efficient EDC degraders with their degradation efficiency exceeding 90% or 80%, respectively, in 7d. Both fungi degraded technical 4-nonylphenol, bisphenol-A, and 17alpha-ethinylestradiol below the detection limit within first 3d of cultivation. In general, estrogenic activities assayed with a recombinant yeast test decreased with advanced degradation. However, in case of I. lacteus, P. ostreatus, and P. chrysosporium the yeast assay showed a residual estrogenic activity (28-85% of initial) in 17alpha-ethinylestradiol cultures. Estrogenic activity in B. adusta cultures temporally increased during degradation of technical 4-nonylphenol, suggesting a production of endocrine-active intermediates. Attention was paid also to the effects of EDCs on the ligninolytic enzyme activities of the different fungi strains to evaluate their possible stimulation or suppression of activities during the biodegradation processes.
- MeSH
- estrogeny aplikace a dávkování farmakologie metabolismus MeSH
- ethinylestradiol aplikace a dávkování metabolismus MeSH
- kongenery progesteronu aplikace a dávkování farmakologie metabolismus MeSH
- kontraceptiva orální kombinovaná aplikace a dávkování farmakologie terapeutické užití MeSH
- kosti a kostní tkáň účinky záření MeSH
- kostní denzita účinky léků MeSH
- lidé MeSH
- menarche MeSH
- mladiství MeSH
- vývoj kostí MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
- Klíčová slova
- MIRELLE (SCHERING, NĚMECKO),
- MeSH
- dospělí MeSH
- ethinylestradiol aplikace a dávkování kontraindikace metabolismus MeSH
- kongenery progesteronu aplikace a dávkování kontraindikace metabolismus MeSH
- kontraceptiva orální hormonální aplikace a dávkování MeSH
- kontraceptiva orální kombinovaná aplikace a dávkování MeSH
- lidé MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
