Citokrom P450- Oksidoreduktaza (POR) v biosintezi holesterola

Translated title of the contribution: Cytochrome P450 - Oxidoreductase (POR) in the biosynthesis of cholesterol

Damjana Rozman, Klementina Fon Tacer

Research output: Contribution to journalArticle

Abstract

Cholesterol has several important physiological functions in mammals and is also indispensable during embryogenesis. Genetic defects of the cholesterol biosynthetic pathway lead to different inborn errors. The phenotypic abnormalities are caused by cholesterol deficiency and accumulation of intermediate sterols. Lanosterol 14α-demethylase (CYP51) catalyses the first step following cyclization of squalene in cholesterol biosynthesis. CYP51 requires cytochrome P450 oxidoreductase (POR) that is the obligate electron donor for the reaction. Some patients with Antley-Bixler syndrome have mutations in the POR gene. A similar phenotype was also observed after early in utero exposure to azoles, which are inhibitors of fungal CYP51 used to treat systemic mycoses. The reason in both cases might be the inhibition of cholesterol biosynthesis on the level of CYP51. The aim of our work was to determine the effect of cytochrome P450- oxidoreductase on cholesterol biosynthesis in liver. We used HPLC analysis to profile sterols (cholesterol, lanosterol, 7-dehydrocholesterol, lathosterol, FF-MAS and T-MAS) in the liver of wild mice and liver specific Por knock-out mice. We show that Por deletion caused strong accumulation of lanosterol. We observed 35-fold induction compared to wild type (397 μg/g vs. 11 μg/g). Despite the buildup of lanosterol, the amount of total liver cholesterol did not change. Our results confirm POR as an obligate and unchangeable electron donor for CYP51 mediated reaction. POR deficiency inhibits lanosterol conversion to FF-MAS as well as cholesterol biosynthesis de novo. Homeostatic mechanisms are able to regulate cholesterol level, most probably through uptake of exogenous cholesterol from diet.

Translated title of the contributionCytochrome P450 - Oxidoreductase (POR) in the biosynthesis of cholesterol
Original languageSlovenian
Pages (from-to)380-384
Number of pages5
JournalFarmacevtski Vestnik
Volume64
Issue number5
StatePublished - Dec 1 2013

Keywords

  • Antley-Bixler syndrome
  • CYP51
  • Cholesterol
  • Cytochromes P450
  • Lanosterol

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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  • Cite this

    Rozman, D., & Fon Tacer, K. (2013). Citokrom P450- Oksidoreduktaza (POR) v biosintezi holesterola. Farmacevtski Vestnik, 64(5), 380-384.