cyp2c19 pm as a possible diabetic rethinopaty risk
TRANSCRIPT
8/11/2019 CYP2C19 PM as a Possible Diabetic Rethinopaty Risk
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Dubravko Kovačević
Kanita Muhić
Sabina Semiz
Adlija Čaušević University in Sarajevo: Faculty of Pharmacy
CYP2C19 PM as a possible diabetic
rethinopaty risk marker in women
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Theme of the presentation
Could CYP2C19 PM be the diabetic
retinopathy risk marker in women?
Why is there sex-determined difference in this
issue?
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Relative Amounts of Individual
Human Hepatic CYPs
Shimada et al ., JPET: 1994
Other
26%
CYP3A
30%
CYP1A2
13%
CYP2E1
7%
CYP2A6
4%
CYP2B6
<1%
CYP2C
18%CYP2D62%
CYP2C9
13.6%
CYP2C19
2.7%
CYP2C8
1.7%
Lasker et al ., Arch. Bioch. Biophys:1998
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CYP2C19
Currently there are eight different alleles of theCYP2C19 gene described, of which seven code
for inactive versions of the enzyme.
wildtype allele:CYP2C19*1;mutated
alleles:CYP2C19*2 to*8
Individuals can be characterized as:
- extensive (EMs) metabolizers
- poor metabolizers (PMs)FACT : Between 2-5% of Caucasians, and 20%
Asians are PMs for CYP2C19 catalysed drug
metabolism
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Diabetic retinopathy (DR)
It is most frequent complication of diabetes
The most common cause of blindness 4.1 million people in USA only have it
We need good risk markers so that we can prevent it on
time
Proliferative (more severe) form of DR
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EETs and 19-HETE
Epoxyeicosatrienoic acids and 19-hydroxyeicosatrienoic
acid – endogenous molecules that are important for
vasodilatative function – especially in retinalmicrocirculation
Bad vasodilatation in retina could be the way of damaging
retinal tissue in DR
Those components are produced by CYP2C19 oxidation
od arachidonic acid
CYP2C19 PMs have less EETs, and therefore threathened
vasodilatative function in retina ???
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new retinal blood vessels
generated in hypoxia
this positive effect does not
occur when we inhibit EETs by EEZE (the inhibitor ofEETs)
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Wang and co. (2011)
They studied the importance of 19-HETE, which is a typeof EET
It acts as a inhibitor of 20-HETE, which has bad effects on
retinal hemodynamics
They have proved that inhibition of 20-HETE improves
retinal hemodynamics in diabetes (diabetic rats): rats without 20-HETE inhibition was diminished by 30-40%
rats with 20-HETE inhibition was diminished by only 5-10%
- This is a proof of positive effect of 19-HETE on retina.
- 19-HETE is also produced by CYP2C19, so PMs could have less protection fr
diabetic retinopathy provided by 19-HETE.
- However, these studies were carried out on rats – larger study on humans wasneeded.
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Kajiwara and co. (2013)
The first and only study on humans discussing this issue
Carried out on 383 Japanese diabetic patients
A clinic-based retrospective longitudinal study
After association studies, and adjustments of sex,
diabetes duration, hipertension, BMI, HbA1c etc., the
results said that f e m a l e CYP2C19 PMs and IMs
were exposed to significantly greater risk of DRdevelopement in relation to EM males.
CYP2C19 PM is identified as an independent risk
factor for DR in women, after stratification by sex
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SexCYP2C19
genotype
Unadjusted odds
ratio (OR);
pp=95%
p-value
Adjusted
odds ratio
(OR); pp=95%
p-value
Male
EM 1 - 1 -
IM 1,61 (0,88-2,95) 0,121,63 (0,85-
3,12)0,14
PM 1,24 (0,58-2,62) 0,581,60 (0,75-
3,43)0,23
Female
EM 1,33 (1,66-2,71) 0,431,78 (0,85-
3,74)0,13
IM 1,94 (0,96-3,97) 0,072,43 (1,17-
5,06)0,02
PM 4,87 (1,79-13,28) 0,0027,49 (2,64-
21,26) <0,001
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Sex difference discussion
PM had much greater impact on DR risk than BMI,blood pressure, HbA1c or diabetes duration – but in
women only!
Why?
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Zhang and co. (2012)
Study carried out on mesenteric arteries of diabeticrats.
Showed that EETs are very important for endothelial
vasodilatative function IN WOMEN
In contrast, males are not so dependent of EETs,
but on other molecules like NO.
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Therefore:
CYP2C19poormetabolism
DiminishedEETssynthesis
Impaired
retinalprotectionin diabetes
Males – not at riskbecause they can
rely on agentsother than EETs
Females – atgreater risk of DR
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Further investigations needed
These results and conclusions are not to be taken
for granted, as greater studies and further
investigations are needed to verify these results.
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