تعدد الاشكال الوراثية لناقل ABCG2 وعلاقته بالاستجابة العلاجية للنيتروفيورانتوين في الاطفال المصابين بالتهاب المسالك البولية في عيادات ومستشفيات مختارة في محافظة كربلاء

Genetic Polymorphism of ATP Binding Cassette G2 (ABCG2) Transporter and the Relationship with Therapeutic Response of Nitrofurantoin in Children with Urinary Tract Infection in Selected Clinics/Hospitals in Kerbala Province

Abstract

Background:
The urinary tract (UTI) is one of the most common area of bacterial infection in humans. The infection of lower urinary tract (UTIs), such as cystitis, are always characterized by symptoms such as frequent urination, urgency, and difficulty urinating. If left untreated, these infections can develop into upper urinary tract infections called acute pyelonephritis or kidney infections.
Nitrofurantoin is a synthetic nitrofuran antibacterial agent that has been used for more than 50 years. It still works and continues to be prescribed, especially in outpatient settings for uncomplicated urological patients, particularly in its microcrystalline formulation, macrodantin.
The ABCG2 gene located on chromosome 4q22 encodes 655 BCRP amino acid breast cancer resistance proteins. Like other G subfamily proteins of the ABC-binding transporter (ABC), BCRP is a semi transporter containing a nucleotide-binding domain and a transmembrane domain fused to a single polypeptide chain. BCRP has a homodimer-like functional form with a molecular weight of 144 kDa. The ABCG2 variant, rs2231142, leads to change of nucleotide cytosine to adenine ABCG2 C421A, a single nucleotide polymorphism associated with decreased protein expression/transport activity in vitro and higher anti‐cancer drug concentrations in carriers of the C421A polymorphism.
Objectives:
The present study was designed to evaluate the possible association of ATP- binding cassette G2(ABCG2) genetic polymorphism (rs 2231142) with susceptibility to urinary tract infection. Also to evaluate the possible association of ABCG2 genetic polymorphism (rs 2231142) with the therapeutic response to nitrofurantoin (after 1 week of 5-7mg/kg daily
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nitrofurantoin treatment) for pediatric with urinary tract infection in clinics/hospitals in kerbala province.
Patients and Methods:
The study is accomplished by enrolling 110 individuals both male and females aged between 4-14 years, diagnosed with UTI and conducted from outpatient in karbala teaching hospital of pediatrics, Al-hussienia hospital and private clinic of pediatric .A mean dose of nitrofurantoin 6mg/kg/day was administered for 1 week , Blood samples were obtained from eligible patients who had given consent for genetic testing. Also urine collected from the same group and two reading of general urine exam were collected, first reading before treatment, and second reading after 1 week. The genetic variant, and ABCG2C421A genes were carefully selected according to the specialized database, genotype was determined by AS-PCR technique, response of drug measured by clinical, RBC, pus, Leukocyte esterase test , nitrite test.
Results:
This study results was recorded the homozygote wild type (CC allele) 34 cases (30.9%), heterozygote (AC allele) 54 cases (49.1%) and 22 cases homozygote mutant type (AA allele)(20% ) on the other hand, the analysis of the effect of the genetic polymorphism on the response to the drug under the study revealed that there was no statistical significant difference of SNPs genotypes (CC, CA and AA) and the response to treatment.
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Conclusion:
The current study concludes that nitrofurantoin did not interact with ABCG2 gene polymorphism(rs2231142) in selected clinics/hospitals in kerbala province in urinary tract infection children and regardless of genotype. These results indicate that nitrofurantoin is not a suitable clinical probe substrate for assessing BCRP activity.
Nitrofurantoin is very effective in these subjects.