Akademik Veri Yönetim Sistemi
Tezin Türü: Yüksek Lisans
Tezin Yürütüldüğü Kurum: Pamukkale Üniversitesi, Fen-Edebiyat Fakültesi, Biyoloji Bölümü, Türkiye
Tezin Onay Tarihi: 2016
Tezin Dili: Türkçe
Öğrenci: Elif Kale
Danışman: Alaattin Şen
Özet:
5-aminosalicyclic acid (5-ASA) is an effective drug that is currently
used for treating diseases such as inflammatory bowel diseases (IBD) and
particularly ulcerative colitis. It is known to be mainly metabolized
by the acetylation via Phase II enzymes. However, there was no clear
information on whether 5-ASA metabolized by cytochrome P450 enzymes or
not. In this study, the possible metabolism of 5-ASA by the microsomal
enzymes of drug metabolizing cytochrome P450s (CYPs) was examined beyond
that N-acetylation pathway. 5-ASA was incubated in vitro with pure CYP
isozymes (CYP1A2, CYP2C9, CYP3A4, CYP2D6, CYP2C19) to determine whether
it acts as a substrate and/or inhibitor for selective P450. For this
purpose, a method was developed and optimized for quantitative
measurement of the 5-ASA calorimetrically in reaction medium. It has
shown that 5-ASA acted as a substrate for the CYP3A4 and CYP2D6
isoforms. The incubation of pure CYP isoforms together with 5-ASA have
led to inhibition of prototype activities of CYP3A4 and CYP1A2, namely
erythromycin N-demethylase and methoxyresorufin O-demethylase
activities, respectively, as compared to selective prototype inhibitors
of P450 isozymes. It was suggested that the 5-ASA is both substrate and
inhibitor for CYP3A4, a substrate for CYP2D6 and inhibitor for CYP1A2.
These are the new contributions to the literature. In addition to the
metabolism of 5-ASA by selected CYP isoforms, the effect of 5-ASA on the
gene expression profiles of selected genes in the HepG2 and Caco-2 cell
lines were investigated by applying qPCR. 5-ASA suppressed the
expression of genes that cause inflammation along with affecting several
oncogenes. The tumor suppressor genes and the genes that take part in
cell signaling and apoptosis were also affected in a way that the cell
health and viability was promoted. This study has provided new clues
for further studies required to be carried out to clarify the effect of
5-ASA as drug-drug interaction and drug-gene interactions.