CYP2C19 PM as a Possible Diabetic Rethinopaty Risk

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



Theme of the presentation

Could CYP2C19 PM be the diabetic

retinopathy risk marker in women?

Why is there sex-determined difference in this

issue?



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



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



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



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 ???





new retinal blood vessels

generated in hypoxia

this positive effect does not

occur when we inhibit EETs by EEZE (the inhibitor ofEETs)



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.



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



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





Sex difference discussion

PM had much greater impact on DR risk than BMI,blood pressure, HbA1c or diabetes duration – but in

women only!

Why?



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.



Therefore:

CYP2C19poormetabolism

DiminishedEETssynthesis

Impaired

retinalprotectionin diabetes

Males – not at riskbecause they can

rely on agentsother than EETs

Females – atgreater risk of DR



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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CYP2C19 PM as a Possible Diabetic Rethinopaty Risk