Genski polimorfizam CYP2D6 i metabolizam ksenobiotika

master's thesis

• Title (english): Genetic polymorphism of CYP2D6 and metabolism of xenobiotics
• Author: Paula Bilušić
• Mentor: Tamara Božina (mentor)
• Committee member: Mila Lovrić (predsjednik povjerenstva)
• Committee member: Ivančica Delaš (član povjerenstva)
• Committee member: Tamara Božina (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Medical Chemistry, Biochemistry and Clinical Chemistry); Zagreb
• Defense date and country: 2021-07-16, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Medical Biochemistry
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Clinical Biochemistry

Abstract

Citokrom P450 2D6 (CYP2D6) je enzim koji sudjeluje u prvoj fazi biotransformacije ksenobiotika i endogenih molekula. Odgovoran je za metabolizam više od 25% lijekova. Gen za CYP2D6 nalazi se na kromosomu 22, lokaciji 22q13.1 i sadrži 9 egzona koji kodiraju 497 aminokiselina. Karakteristika gena CYP2D6 je njegova izrazita podložnost varijabilnostima, što je važno u kliničkoj praksi, s obzirom na to da CYP2D6 sudjeluje u metabolizmu velikog broja lijekova. Za polimorfizme CYP2D6 karakteristična su četiri metabolička fenotipa. Normalni metabolizatori zastupljeni su u otprilike 60 – 75%, a intermedijarni metabolizatori u 25 – 40% populacije. Incidencija sporih metabolizatora je 5 – 10% u bijeloj i crnoj afričkoj populaciji, a 1% u azijata. Vrlo brzi metabolizatori prisutni su u 1 – 10% bijele populacije. Najučestaliji nefunkcionalni alel je CYP2D6*4 i nalazimo ga u otprilike 20% Europljana, dok ga u Azijata gotovo nema. U Azijata je najzastupljeniji alel smanjene funkcije CYP2D6*10 (40%). Genetička varijabilnost u genu CYP2D6 može znatno utjecati na ishod i učinkovitost terapije lijekovima koji se metaboliziraju putem CYP2D6. Kod sporih metabolizatora koncentracija lijeka u plazmi je povećana, što može potaknuti razvoj štetnih nuspojava. Kako bi se spriječio razvoj nuspojava, preporučeno je smanjiti dozu lijeka kod sporih metabolizatora. S druge strane, kod vrlo brzih metabolizatora koncetracija lijeka u plazmi je smanjena i to može uzrokovati neadekvatan odgovor na terapiju. To se može prevenirati povećanjem doze lijeka kod vrlo brzih metabolizatora. Neki lijekovi prevode se u farmakološki aktivne metabolite tek djelovanjem enzima CYP2D6 i tada spori metabolizatori imaju smanjene razine aktivnih metabolita, što dovodi do smanjenog terapijskog učinka, a vrlo brzi metabolizatori imaju povišene razine aktivnog metabolita te je moguć razvoj nuspojava. Danas postoje smjernice za odabir lijeka i doziranje prema genetičkom profilu pojedinca.

Abstract (english)

Cytochrome P450 2D6 (CYP2D6) is an enzime which participates in the first phase of biotransformation of xenobiotics and endogenous molecules. It is responsible for the metabolism of more than 25% drugs. CYP2D6 gene is located on chromosome 22, locus 22q13.1 and it contains 9 exons encoding 497 amino acids. Characteristic of CYP2D6 gene is its pronounced susceptibility to variabilities which is important in clinical practice, because CYP2D6 is involved in the metabolism of a large number of drugs. CYP2D6 polymorphisms are characterized by four metabolic phenotypes. Normal metabolizers are present in approximately 60 – 75%, and intermediate metabolizers in 25 – 40% of the population. The incidence of slow metabolizers is 5 – 10% in white and black African populations, and 1% in Asians. Ultra rapid metabolizers are present in 1 – 10% of the white population. The most common non–functional allele is CYP2D6*4 and is found in approximately 20% of Europeans, while it is almost absent in Asians. In Asians, the allele of reduced function CYP2D6*10 (40%) is the most common. Genetic variability of CYP2D6 gene may significantly affect the outcome and efficacy of therapy with drugs metabolized by CYP2D6. In slow metabolizers, the plasma concentration of drug is increased, which may induce the development of harmful side effects. To prevent the development of side effects, it is recommended to reduce the dose of a drug in slow metabolizers. On the other hand, in ultra rapid metabolizers, plasma drug concentration is reduced and this may cause an inadequate response to therapy. This can be prevented by increasing the dose of a drug in ultra rapid metabolizers. Some drugs are remodeled into pharmacologically active metabolites only by the action of the enzyme CYP2D6. In that case slow metabolizers have reduced levels of active metabolites resulting in reduced therapeutic effect, and very fast metabolizers have elevated levels of active metabolite and the development of side effects is possible. Guidelines for drug selection and dosing according to an individual’s genetic profile are available.

• Keywords: genski polimorfizam; CYP2D6; ksenobiotici; lijekovi; doziranje
• Keywords (english): genetic polymorphism; CYP2D6; xenobiotics; drugs; dosing
• Language: croatian
• URN:NBN: urn:nbn:hr:105:029190
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Public note: Pohranitelj objekta unio ključne riječi.
• Created on: 2022-01-21 11:10:37