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Objective To investigate the clinical and pathological features of progressive familial intrahepatic cholestasis type 3 (PFIC3). Methods A retrospective analysis was performed for 1326 patients with unexplained liver disease who attended Nanjing Second Hospital from January 2017 to December 2019, among whom 8 patients were diagnosed with PFIC3 based on clinical/pathological manifestation and gene sequencing results (1 patient did not undergo liver biopsy due to contraindication). Clinical, laboratory, imaging, and pathological findings were analyzed and a literature review was performed for the pathology of ABCB4-related diseases to summarize the clinical and pathological features of PFIC-3. Results Among the 8 patients with PFIC3, there were 5 male patients and 3 female patients, with a median age of 29.5 years. Of all 8 patients, 4 (50%) manifested as chronic cholestasis and 4 (50%) manifested as biliary cirrhosis, among whom 3 (75%) had the manifestation of portal hypertension. As for biochemical examination, 75% (6/8) had an increase in alkaline phosphatase, and 100% (8/8) had an increase in gamma-glutamyl transpeptidase. As for imaging examination, 50% (4/8) had cholecystitis, 25% (2/8) had gallstones, 25% (2/8) had bile duct dilatation, 75% (6/8) had splenomegaly, and 25% (2/8) had liver cirrhosis. As for liver biopsy, all 7 patients manifested as bile duct injury and/or reduction, and 57.1% (5/7) had absence of the bile duct. Multidrug resistance P-glycoprotein 3 (MDR3) immunohistochemical staining showed normal expression in 42.9% (3/7) of the patients and reduced expression in 57.1% (4/7) of the patients. Literature review obtained 17 articles with a description of the bile duct or MDR3 immunohistochemistry. Among the 7 patients with low phospholipid-associated cholelithiasis, 71.4% (5/7) had normal bile duct, 14.3% (1/7) had bile duct reduction, and 14.3% (1/7) had absence of the bile duct; among the 6 patients with intrahepatic cholestasis of pregnancy, 16.7% (1/6) had normal bile duct, 50% (3/6) had bile duct reduction, and 33.3% (2/6) had absence of the bile duct; among the 8 patients with PFIC3, 25% (2/8) had bile duct reduction and 75% (6/8) had absence of bile duct; among the 21 patients with PFIC3, 9.5% (2/21) had normal expression of MDR3, 23.8% (5/21) had a reduction in the expression of MDR3, and 66.7% (14/21) had absence of the expression of MDR3. Conclusion PFIC3 mainly manifests as cholestasis, cholelithiasis, and hepatic fibrosis. Pathological manifestation includes bile duct injury and bile duct reduction or absence of the bile duct in severe cases, and the degree of injury is associated with disease severity. MDR3 immunohistochemistry may show normal expression, reduced expression, or absence of expression, and diagnosis cannot be excluded in patients with normal expression. Genetic testing can be performed for diagnosis when necessary.
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Objects To investigate the correlation of the single nucleotide polymorphism ( SNP) of clopidogrel related gene CYP2C19, ABCB1, PON1 to the occurrence of clopidogrel resistance ( CR) and TEG among patients after percutaneous coronary intervention.Methods A total of 299 patients after PCI were enrolled from April 2015 to December 2015.It genotyped the CYP2C19(rs4244285,rs4986893)ABCB1 ( rs1045642 ) and PON1 ( rs662 ) gene, measured clopidogrel response by TEG.Accordingly, all the enrolled 299 patients were then divided into CR group (n=17) +non-CR (NCR) group (n=282) or CLR group (n=54) +non-CR (NCR) group (n=245) by TEG(%).All the patients were divided into EM、IM and PM group by CYP2C19 genotype.The age of patient in CR (71.1 ±11.1) years old is higher than NCR (65.02 ±10.51) years old (t=2.559, P0.05).There was no significant difference between CR(χ2 =0.175,P=0.916) CLR(χ2 =1.589,P=0.452)and the level of TEG(ADP) (Z=-0.030,P=0.976) in PON1(rs662) polymorphism.There was no significant difference between CR(χ2 =1.722,P=0.423) CLR(χ2 =0.176,P=0.916) and the level of TEG(ADP) (Z=-0.331,P=0.741) in ABCB1(rs1045642) polymorphism.Conclusions CYP2C19 PM is associated with decreased of TEG(ADP).It is considered that no correlation exists between ABCB1(rs1045642) and PON1(rs662) polymorphism and clopidogrel resistance in patients with coronary heart diseases.The loss of function of ABCB1 ( rs1045642 ) and PON1 ( rs662 ) is not associated with decreased of TEG(ADP) in CYP2C19 PM patients.
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OBJECTIVE: The multidrug resistance 1 (ABCB1, MDR1) gene, encoding P-glycoprotein, is extensively distributed and expressed in various tissues, such as a blood-brain barrier transporter. P-glycoprotein plays an important role in controlling the passage of substances between the blood and brain. The current study aimed to investigate possible associations of functional ABCB1 polymorphisms (C3435T, G2677T and C1236T) with response to antidepressant treatment and serum cortisol levels in Taiwanese patients with major depressive disorder (MDD). METHODS: We recruited 112 MDD patients who were randomized to fluoxetine (n=58, mean dose: 21.4+/-4.5 mg/day) or venlafaxine (n=54, 80.2+/-34.7 mg/day) treatment for 6 weeks. The 21-item Hamilton Depression Rating Scale (HDRS) was administered initially and biweekly after treatment, and cortisol levels were assessed initially and after 6-week antidepressant treatment. RESULTS: The initial HDRS scores and the HDRS scores after six weeks of antidepressant treatment were not significantly different among the different genotypes in each polymorphism of ABCB1. The percentage changes of HDRS scores over time were significantly different in the polymorphisms of ABCB1 G2677T (p=0.002). MDD patients with the G/G genotype of ABCB1 G2677T had a worse antidepressant treatment response. However, the polymorphisms of ABCB1 genotypes were not significantly associated with cortisol levels before and after antidepressant treatment in MDD patients. CONCLUSION: The results suggested that the variants of ABCB1 may influence the short-term antidepressant response in MDD patients. Further details of the underlying mechanisms of ABCB1 in antidepressant treatment remain to be clarified.
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Humans , Antidepressive Agents , Blood-Brain Barrier , Brain , Depression , Depressive Disorder, Major , Drug Resistance, Multiple , Fluoxetine , Genotype , Hydrocortisone , ATP Binding Cassette Transporter, Subfamily B, Member 1 , ATP Binding Cassette Transporter, Subfamily B , Venlafaxine HydrochlorideABSTRACT
OBJECTIVE: To investigate the regulation effect of isoniazid on the hepatobiliary membrane transporters multidrug resistance protein 2 (Mrp2), bile salt export pump (Bsep), P-glycoproteins (P-gp), sodium taurocholate cotransporting plypeptide (Ntcp), and which would lay the foundation for the studies of the mechanism on isoniazid-induced liver injury from the level of transporters. METHODS: Following an oral dose of 30, 60, 120 mg · kg-1 · d-1 for 1, 2 and 3 months in mouse respectively, the biochemical indicator of serum were determined; the liver were removed for hepatic pathology; the protein mass of Bsep, Mrp2, Ntcp and P-gp were analyzed by Western Blotting. RESULTS: After high/middle/low dose isoniazid administration, the expression of Mrp2, Bsep, P-gp and Ntcp were all changed, especially the high/middle dose group. In addition, the biochemical and pathological were significantly lagged behind the expression change of the transporters. CONCLUSION: The hepatotoxicity of isoniazid may be associated with excessive hepatic accumulation of the related exogenous substances that medicated by Mrp2, Bsep, P-gp and Ntcp.
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Objective To investigate the impact of multi-drug transporters including P-glycoprotein (PGP) and multi-drug resistance associated protein (MRP) on concentration of lamotrigine in the extracellular fluid in hippocampus of epilepsy rat models induced by pilocarpine, and to deduce the multi-drug resistance mechanisms in refractory epilepsy. Methods The epilepsy rat models were established by repeated administration (by ip) of pilocarpine. A microdialysis probe was placed into the hippocampus of the epileptic rats and dialysate was collected at five time-points from 30--150 minutes after systemic injections of lamotrigine (10 mg/kg). The concentration of lamotrigine in the extracellular fluid in the hippocampus was determined by high-performance liquid chromatography (HPLC). Then PGP inhibitor verapamil and MRP inhibitor probenecid was added individually through microdialysis probe and the concentration of lamotrigine was detected again. Results Compared with control group (0. 41 ± 0. 10 in 60 minutes, 0. 50 ±0.04 in 90 minutes, 0. 39 ±0. 09 in 120 minutes and 0. 30±0.06 in 150 minutes), verapamil significantly increased the concentration of lamotrigine in extracellular fluid of the hippocampus 60--150 minutes (0. 65 ±0. 11, 0. 84 ± 0. 09, 0. 70± 0. 09 and 0. 58 ± 0. 08 respectively) after injection (F value were 5.01, 8.61, 10. 23 and 7.89, all P < 0. 05) and probenecid also enhanced the concentration of lamotrigine 90--150 minutes (0. 75 ± 0. 09, 0. 58±0. 10 and 0. 49±0. 07) after injection (F = 6. 58, 4. 56, 4. 75, all P < 0. 05). Conclusions Penetration of lamotrigine through blood-brain barrier in pilocarpine induced epilepsy rats is restricted by PGP and MRP, resulting in decreased concentration of lamotrigine in the extracellular fluid of the hippocampus. Therefore, increasing expression of PGP and MRP in brains of epilepsy patients might be an important mechanism involved in multi-drug resistance in refractory epilepsy.
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Objective To explore the expression of drug transporter organic anion transporting polypeptide2(Oatp2) and P-glycoprotein(P-gp) in brains of chronic epileptic rats induced by lithium-pilocarpine.Methods Chronic epilepsy modles were elicited after status epilepticus(SE) induced by lithium-pilocarpine in adult Wistar rats.The expressions of Oatp2 and P-gp were detected by immuno-histochemistry(SABC) method.Results Positive expression of Oatp2 was predominantly in the plexus epithelial cells and(blood-brain) barrier endothelial cells.Weak staining for Oatp2 was also detected in the neurocyte.In contrast,apparent expression of(P-gp) was seen in brain capillary and neurocyte only.Compared with normal control rats,expression of Oatp2 on the plexus epithelial cells and brain capillary in chronic epileptic rats was significantly decreased(P
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0.05),respectively. Conclusion: The results indicate that the multidrug resistance of MEC-1/5Fu may be related to the higher expression of P-gp170 protein.
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Objective:To study the expression and significance of P-gp and GST-?in colorectal carcinoma.Methods: Immunohistochemistry was used to examine the P-gp and GST-?expression in 78 cases of colorectal carcinoma and 31 cases of normal colorectal tissues.Resu/ts:The positive expression rates of P-gp and GST-?in colorectal carcinoma were 83.3% and 85.9% respectively,higher than those in normal colorectal tissues.The expression of P-gp was related to the degree of invasion(P