INFLUENCE OF POTENTIAL GENE POLYMORPHISMS
ON PROPOFOL DOSAGE REGIMEN IN PATIENTS
UNDERGOING ABDOMINAL HYSTERECTOMY
Ivanov E, Sterjev Z, Budic I, Nojkov J, Karadzova D, Sivevski A
*Corresponding Author: Emilija Ivanov, Prim. M.Med., University Clinic for Gynecology and Obstetrics,
University “Ss Cyril and Methodius” Medical Faculty, Mother Theresa, Skopje, Republic of North
Macedonia. Tel./Fax: +389-(0)-23-228-440. E-mail: emilijaivanov@gmail.com
page: 41
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DISCUSSION
In this study, we evaluated the possible influence of
three functional SNPs in genes with potential influence
on propofol pharmacokinetics and/or pharmacodynamics,
and therefore, on dose requirements for achieving
adequate propofol response. The study was undertaken
in a relatively homogenous group of patients (according
to the ASA physical status classification), who required
treatment at a single University Hospital Clinic, with a strict follow-up of clinical guidelines for administration
of recommended doses of other medications to achieve the
same level of anesthesia depth in all subjects.
The results of previous studies evaluating the association
of individual genetic characteristics of patients with the
dosage and effects of propofol treatment suggest a possible
association of polymorphisms in certain genes with the use
of propofol in daily clinical practice. Conflicting data have
been reported from the clinical studies that evaluated polymorphisms
in genes encoding enzymes involved in propofol
metabolism (CYP2C9, CYP2B6, CYP3A4, UGT1A9)
as well as polymorphisms in genes encoding (GABRA1)
receptor protein and transport protein gene ABCB1 [13,14].
Our study aimed at contributing to the knowledge on the influence
of several SNPs in CYP2B6, GABRA1, and ABCB1
genes on variations in the clinical response of propofol.
The CYP2B6 is one of the most polymorphic CYP
genes in humans. Variants of this gene have been shown
to affect transcriptional regulation, protein expression
and catalytic activity [15]. Some variations seem to affect
several functional levels simultaneously, and thus,
combined in haplotypes, lead to complex interactions between
substrate-dependent and independent mechanisms.
Polymorphism c.516>GT (rs3745274, Gln172His) presents
a modified rearrangement site that results in loss
of exons 4 to 6, leading to a drastic reduction in normal
transcripts and a reduced level of active protein. All this
leads to a reduced metabolism rate of propofol. Our results
indicate that patients with one or two copies of the variant
allele require lower doses of propofol for the induction
and maintenance of anesthesia. We also found that times
for induction and awakening are different among patients with different genotypes for this metabolism. However,
these differences were not statistically significant, most
probably due to the small number of patients in our cohort.
These data are in agreement with the results obtained by
Mourão et al. [7], who also found the possible influence
of the CYP2B6 (c.516G>T) genetic variant on propofol
dose in patients under general anesthesia. A larger study
to clarify this issue is warranted, as it might help in the
stratification of patients for propofol use during anesthesia.
The GABRA1 gene encodes a γ-aminobutyric acid
(GABA) receptor. The GABA receptor is the major inhibitory
neurotransmitter in the mammalian brain where
it acts at a GABAA receptor, which are ligand-gated
chloride channels. The GABRA1 gene mutation leads to
the formation of an abnormal α1 subunit that reduces the
GABAA receptor protein function. The G>A mutation in
rs2279020 on the GABRA1 gene may be able to alter the
pharmacological properties of the receptor by altering the
composition and distribution of subunits. Under propofol
anesthesia, small A-allelic rs2279020 in GABAA1 can induce
stronger brain inhibition, as seen through entropy in
patients after loss of consciousness [16,17]. This result
strongly supports the role of GABAA1 in the sensitivity
of propofol anesthesia. Moreover, the GABAA1 receptor
mutation (rs2279020) also contributes to the different
effects of propofol on blood pressure. The detected
genotypic frequencies for GABRA1 (rs2279020, assay ID
C__15966883_10) in our patients group were 38.0% for
GG, 42.0% AG and 20.0% for AA. Our results have shown
that the frequency of these polymorphisms in our patients
is similar to that in other population studies [18]. In our
study, we found differences between the given propofol
doses in patients with different genotype for the polymorphism
studied. In the case of the GABRE polymorphism
examined, this trend is much more intense compared to
the CYP2B6 gene trend, but still insufficient to obtain a
statistically significant difference, which in our opinion,
is due solely to the number of patients included.
The ABCB1 (MDR1, P-gp) gene is the first identified
and best characterized ABC transporter. This gene encodes
for a transmembrane protein that mediates ATP-dependent
transport of various molecules. The P-gp is the “guardian”
of the brain and is expressed in the luminal surface of the
blood-brain barrier (BBB) capillary endothelial cells. It
enables the transport of toxic compounds out of the brain.
The exon 26 c.3435C>T variant is one of the more than
100 polymorphic variants of this gene that have been discovered
so far. This polymorphism correlates with altered
levels of P-gp expression and a change in drug response
in various clinical conditions [19]. Our data indicates that
the ABCB1 (c.3435C>T) variant does not have any influence
of the clinical parameters in our cohort of patients
who received propofol for anesthesia. Although there are
limited data about the influence of this variant on propofol
therapy, our data is in line with the result published by
Zakerska-Banaszak et al. [20], who also failed to find
statistically significant difference between the propofol
therapeutic effects and the ABCB1 gene variants.
In conclusion, our study did not detect a statistically
significant influence of the CYP2B6 (c.516G>A), GABRA1
(c.1059+15G>A) and ABCB1 (c.3435T>C) gene variants
on the variability of clinical parameters associated with
the use of propofol. We also did not see a statistically
significant difference when we grouped patients by age
or ethnicity. However, the observed trend on the possible
influence of the CYP2B6 (c.516G>A) and GABRA1
(c.1059+15 G>A) variants warrant an extension of these
studies on a larger number of patients [7,8,21].
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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