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Opioids Analgesics and Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
R. Rachana, Tanya Gupta, Saumya Yadav, Manisha Singh
CYPD26, cytochrome P450 2D6; CYP3A, cytochrome P450 3A4; UGT2B7, UDP-glucuronosyltransferase-2B7; C6G, codeine-6-glucuronide; M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronide; ABCC2, ATP-binding cassette sub-family C member 2; ABCC3, ATP-binding cassette sub-family C member 3.
Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
In addition to P-gp, several other members of the ABC gene family also function as drug transporters (47–55). MRP1/ABCC1 confers resistance to anthracyclines, vinca alkaloids and epipodophyllotoxins, and transports glutathione conjugates of drugs (47,48,52–55). None of the other ABC transporters are as strongly associated with clinical endpoints as P-gp/MDR1, and clinical strategies for reversing resistance related to these transporters have not been developed. MRP2/ABCC2, also known as the canalicular multiple organic anion transporter (cMOAT), is highly expressed in the biliary tract, and transports glucuronide and glutathione drug conjugates, including anthracyclines. It is the gene whose deficiency results in the Dubin-Jonson syndrome (51). MRP2 is involved in hepatic excretion of anticancer drugs, but has not been implicated as a resistance factor in cancers (49,55). The MRP3/ABCC3 gene confers resistance to epipodophyllotoxins as well as to methotrexate (50,51), while MRP4/ABCC4 and MRP5/ABCC5 confer resistance to nucleotide analogues and their metabolites (51).
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
HNF-4α is a member of the nuclear receptor superfamily and is mainly expressed in a restricted manner in the liver, intestine, kidney, and pancreas (Mendel and Crabtree 1991). It plays an important role in the regulation of many liver-specific genes, such as those encoding apolipoproteins, coagulation factors, and CYPs that are involved in lipid transport and glucose metabolism, coagulation, and drug metabolism (Chiang 2009; Crestani et al. 2004; Erdmann and Heim 1995; Gonzalez 2008; Gupta and Kaestner 2004; Hwang-Verslues and Sladek 2010; Jover et al. 2009; Mendel and Crabtree 1991; Rana et al. 2010; Walesky and Apte 2015; Wortham et al. 2007). HNF-4α is required for the PXR- and CAR-mediated transcriptional activation of CYP3A4 (Tirona et al. 2003). A DR element with a one-nucleotide spacer located in the proximal promoter region of the CYP2D6 gene plays an important role in modulating CYP2D6 expression, and HNF-4α interacts with this binding element (Cairns et al. 1996). Cotransfection of the minimal CYP2D6 promoter –CAT construct (-392 bp) with a mammalian HNF-4α expression vector results in a 30-fold induction of CAT activity in COS-7 cells. Although HNF-4α is originally identified as an orphan receptor, fatty acyl-CoA thioesters are identified to be endogenous ligands for HNF-4α (Hertz et al. 1998; Petrescu et al. 2002). The binding of ligand may shift the oligomeric–dimeric equilibrium of HNF-4α or may modulate the affinity of HNF-4α for its cognate promoter element, resulting in either activation or inhibition of HNF-4α transcriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands (Petrescu et al. 2002). The HNF-4α binding element is conserved in the proximal promoter regions of more than 20 CYP2 genes (Chen et al. 1994; Ibeanu and Goldstein 1995). Jover et al. (2001) have demonstrated that HNF-4α plays a general role in the regulation of major P450 genes, including CYP3A4, 3A5, 2A6, 2B6, 2C9, and 2D6, in human hepatocytes using antisense technique. Using the small interfering RNA technique, Kamiyama et al. (2007) have found that suppression of HNF-4α causes a decrease in the mRNA levels of CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; UGT1A1 and 1A9; SULT2A1; ABCB1; ABCB11; ABCC2; OATP1B1; and OCT1; as well as those of PXR and CAR. In addition, deletion of HNF-4α decreases debrisoquine 4-hydroxylase activity in CYP2D6-humanized mice more than 50% (Corchero et al. 2001). These findings indicate that HNF-4α may act as a common regulator of the liver-specific transcription of many P450 genes.
Direct antiviral agents (DAAs) and their use in pregnant women with hepatitis C (HCV)
Published in Expert Review of Anti-infective Therapy, 2022
Sandra Abdul Massih, Ahizechukwu C. Eke
Changes in drug transporter activity play significant roles in drug absorption [53]. The most extensively studied intestinal transporters belong to the ATP binding cassette (ABC) family. These include ABCB1, also known as P-glycoprotein (P-gp), ABCG2, also known as breast cancer resistance protein, and ABCC2, called multidrug resistance-associated protein 2 (MRP2) [53]. Almost all the DAA drugs are substrates of P-gp and/or other transporters whose actions can increase or decrease during pregnancy, with the potential to affect drug absorption and bioavailability. Some of these gastrointestinal and hepatic transmembrane transporters undergo changes that occur during pregnancy that can affect the disposition of HCV drugs. For example, OATP1B1/3 is a primary uptake transporter for Grazoprevir (GZR), and there is an approximately 50% decreased expression of OATP1B during pregnancy (as demonstrated in hepatocytes of pregnant rats) [53]. Therefore, it is plausible that due to the decrease in OATP1B expression in the liver/bile ducts during pregnancy, hepatic absorption of GZR would likely decrease during pregnancy. The effects of these drug transporters on HCV drugs during absorption remain unknown and is currently being studied by the International Transport Consortium (ITC).
Therapeutic Perspective of Temozolomide Resistance in Glioblastoma Treatment
Published in Cancer Investigation, 2021
Qin Xia, Liqun Liu, Yang Li, Pei Zhang, Da Han, Lei Dong
In various types of CSCs and normal stem cells, the expression of drug transporters, such as ABC transporters is increased. GSCs expel drugs or decrease the drug uptake through increased expression of the ABC transporter, which is responsible for chemoresistance. ABC transporters transport molecules (such as TMZ) outside the cells, make a population of tumor cells evade treatment, and contribute to tumor recurrence. Warrier et al. found that CSCs resistant to doxorubicin (an anti-cancer drug) expressed elevated levels of ABC transporters, such as ABCG2 (ATP binding cassette subfamily G member 2), ABCC2 (ATP binding cassette transporter C2), and ABCC4 (ATP binding cassette transporter C4), which suggested that ABC transporters play a role in drug resistance (44). Indeed, it was found that compared with differentiated cancer cells, GSCs express ABC transporter channels at a higher rate, which makes the delivery of drugs more challenging due to the BBB and irregular vasculature (45).
Association of polymorphism of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR with the concentration of cyclosporin A in allogeneic haematopoietic stem cell transplantation recipients
Published in Xenobiotica, 2021
Linlin Wang, Guangting Zeng, Jianqiang Li, Jia Luo, Huilan Li, Zanling Zhang
The ABCC2 (multidrug resistance-related protein, MRP) family and ABCG2 (breast cancer resistance protein, BCRP) have been identified as major determinants of chemoresistance in tumour cells (Sefidgar et al.2014). They are expressed in the apical membranes of many barrier tissues such as the intestine, liver, blood brain barrier, thus contributing to plasma, but also intracellular drug disposition. Studies have shown the mutation of rs717620 can lead to reduced MRP transport activity, affect drug metabolism and lead to drug accumulation in vivo (Zhou et al.2005). A significant association was observed between the CsA Cssmin/D and ABCC2 rs717620. We firstly investigated the effect of ABCG2 polymorphism on CsA Cssmin/D and found a significant effect, which suggested that ABCG2 mutation has a notable effect on CsA concentrations. Further study is needed to reveal the underlying mechanisms.