Analiza ekspresije gena koji kodiraju sintezu enzima CYP3A4, CYP2B6, i ABCB1 transportera kod bolesnika sa HIV i HCV infekcijom lečenih antivirusnim lekovima

[B. Obradović]

75 str.

Medicine - Medical pharmacology / Medicinske nauke - Medicinska farmakologija

Background: The superfamily of CYP P450 enzymes and the family of ABC transporters are essential in determining how antiretroviral drugs and anti-HCV drugs are processed affecting further therapeutic success of occurrence of adverse effects. Among these enzymes, CYP3A4 is the most widely distributed metabolic enzyme, predominantly found in the small intestine and liver is responsible for metabolizing various drug classes, including protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and CCR5 receptor antagonists. On the other hand, CYP2B6 plays a significant role in processing nucleoside reverse transcriptase inhibitors, such as efavirenz. ABC transporters are also involved in all stages of drug pharmacokinetics and can be found in different tissues and organs such as the brain, liver, and small intestine. ABCB1, in particular, acts as a transporter for a wide range of substances, including several antiretroviral drugs and integrase inhibitors. However, studies have revealed notable variations in the activity of CYP P450 enzymes and the ABC transporter system due to liver tissue damage or applied therapeutics. These variations often manifest as changes in mRNA levels and protein expression in different pathological conditions. Since HCV co-infection is common among people living with HIV due to similar transmission routes, there are approximately 5 million registered cases of HIV/HCV co-infection worldwide. Research has demonstrated that HIV infection accelerates the progression of liver damage in co-infected patients with HCV. Recent studies have suggested that the extent of liver fibrosis can also impact the activity of the CYP enzyme system, in addition to genetic factors. The level of inflammation in liver tissue serves as an indicator of the acute intensity of infection, liver damage, and response to treatment protocols. In vitro and animal studies have shown that inflammation affects the activity of CYP P450 enzymes and the ABC transporter family through complex transcriptional and post-transcriptional mechanisms. The activity of metabolic enzymes and transporters is believed to be dependent on the nature and duration of inflammatory mediators. Three proposed mechanisms explain how inflammation alters the activity of metabolic enzymes and transporters: activation of the nuclear factor-kB (NF-kB) pathway by pro-inflammatory cytokines, leading to transcriptional inhibition; post-transcriptional mechanisms involving enzyme degradation through nitric oxide synthesis; and epigenetic modifications, such as changes in methylation processes in the promoter regions of enzymes and transporters. Considering that many drugs used for HIV and HCV treatment are primarily metabolized by these enzymes and transporters, it is crucial to investigate the impact of chronic inflammation, liver damage, and long-term therapy on their activity levels. Any changes in the activity of metabolic enzymes and transporters pose risks for adverse or toxic effects of antiretroviral and anti-HCV medications, as well as the potential failure to achieve therapeutic drug concentrations. This risk is particularly significant in the treatment of chronic infections characterized by rapid viral replication and immune evasion...

farmakokinetskim procesima kojima podležu antiretrovirusni lekovi i lekovi protiv hepatitis C virusne infekcije, što ima značajni efekat na uspeh terapije i pojavu neželjenih efekata. Među tim enzimima, CYP3A4 je najrasprostranjeniji metabolički enzim, koji se dominanto nalazi u jetri i tankom crevu, a odgovoran je za metabolizam različitih klasa lekova, uključujući inhibitore proteaze, nenukleozidne inhibitori reverzne transkriptaze i antagoniste CCR5 receptora. Sa druge strane, CYP2B6 ima značajnu ulogu u metabolisanju nukleozidnih inhibitora reverzne transkriptaze, poput efavirenza. ABC transporteri takođe su uključeni u sve faze farmakokinetike lekova i mogu se naći na različitim tkivima i organima kao što su mozak, jetra i tanko crevo. ABCB1, posebno, funkcioniše kao transporter za širok spektar supstanci, uključujući nekoliko antiretrovirusnih grupa lekova, poput inhibitora integraze. Međutim, istraživanja su pokazala značajne varijacije u aktivnosti enzima CYP P450 i ABC transportera usled oštećenja tkiva jetre ili hronične primene terapije. Ove varijacije se često manifestuju kao promene nivoa iRNK i ekspresije proteina u različitim patološkim stanjima kao što su hronične virusne infekcije. Budući da je ko-infekcija HCV-om česta kod osoba koje žive sa HIV-om zbog sličnih puteva prenosa, širom sveta zabeleženo je oko 5 miliona registrovanih slučajeva ove ko-infekcije. Podaci iz dostupne literature su pokazali da HIV infekcija ubrzava progresiju oštećenja jetre kod ko-inficiranih pacijenata sa HCV-om. Nedavne studije su ukazale da stepen fibroze jetre takođe može uticati na aktivnost metaboličkih enzima, pored genetičkih faktora. Nivo inflamacije u jetri takodje služi kao pokazatelj akutnog intenziteta infekcije, oštećenja jetre i odgovora na terapijske protokole. In vitro i animalne studije su pokazale da inflamacija utiče na aktivnost enzima CYP P450 i familije ABC transportera putem složenih transkripcionih i posttranskripcionih mehanizama. Veruje se da je aktivnost metaboličkih enzima i transportera zavisna od prirode i trajanja inflamatornih medijatora. Predložena su tri mehanizma kojima inflamacija utiče na aktivnost metaboličkih enzima i transportera: aktivacija nuklearnog faktora-kB (NF-kB) putem proinflamatornih citokina, što dovodi do transkripcionog inhibiranja; posttranskripcioni mehanizmi koji uključuju degradaciju enzima putem sinteze azot monoksida; i epigenetičke modifikacije, kao što su promene u metilaciji u promotorskim regionima enzima i transportera. Kako se mnogi antiretrovirusni i lekovi koji se koriste u terapiji HCV infekcije metabolišu putem ovih enzima i transportera, od suštinske je važnosti istražiti uticaj hronične inflamacije, oštećenja jetre i dugotrajne terapije na njihovu aktivnost. Svaka promena u aktivnosti metaboličkih enzima i transportera predstavlja rizik od neželjenih ili toksičnih efekata kao i potencijalnog neuspeha u postizanju terapijskih koncentracija leka. Ovaj rizik je posebno značajan u lečenju hroničnih infekcija koje karakteriše brza replikacija i visoka mutagenost virusa...

metabolic enzymes, metabolic transporters, HIV, HCV, gene expression, chronic inflammation, liver fibrosis, CYP3A4, CYP2B6, ABCB1

metabolički enzimi, metabolički transporteri, HIV, HCV, ekspresija gena, hronična inflamacija, fibroza jetre, CYP3A4, CYP2B6, ABCB1

615.281:577.2(043.3)

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