Elsevier

Pharmacology & Therapeutics

Volume 159, March 2016, Pages 35-55
Pharmacology & Therapeutics

Associate Editor: B. Teicher
The role of glucuronidation in drug resistance

https://doi.org/10.1016/j.pharmthera.2016.01.009Get rights and content

Abstract

The final therapeutic effect of a drug candidate, which is directed to a specific molecular target strongly depends on its absorption, distribution, metabolism and excretion (ADME). The disruption of at least one element of ADME may result in serious drug resistance. In this work we described the role of one element of this resistance: phase II metabolism with UDP-glucuronosyltransferases (UGTs). UGT function is the transformation of their substrates into more polar metabolites, which are better substrates for the ABC transporters, MDR1, MRP and BCRP, than the native drug. UGT-mediated drug resistance can be associated with (i) inherent overexpression of the enzyme, named intrinsic drug resistance or (ii) induced expression of the enzyme, named acquired drug resistance observed when enzyme expression is induced by the drug or other factors, as food-derived compounds. Very often this induction occurs via ligand binding receptors including AhR (aryl hydrocarbon receptor) PXR (pregnane X receptor), or other transcription factors. The effect of UGT dependent resistance is strengthened by coordinate action and also a coordinate regulation of the expression of UGTs and ABC transporters. This coupling of UGT and multidrug resistance proteins has been intensively studied, particularly in the case of antitumor treatment, when this resistance is “improved” by differences in UGT expression between tumor and healthy tissue. Multidrug resistance coordinated with glucuronidation has also been described here for drugs used in the management of epilepsy, psychiatric diseases, HIV infections, hypertension and hypercholesterolemia. Proposals to reverse UGT-mediated drug resistance should consider the endogenous functions of UGT.

Introduction

Enzymatic systems are necessary to transform nonpolar endogenous and exogenous compounds into their hydrophilic derivatives. This metabolism aims to impair the undesired accumulation of lipophilic agents, facilitating their excretion outside the organism or out of cells. The majority of exogenous compounds (xenobiotics) undergo phase I metabolism, which leads to more polar and more reactive compounds. They are prepared to be better substrates for phase II metabolic enzymes. However, the substrates for phase II metabolic enzymes are not only xenobiotics, but also many endogenous compounds that play crucial functions in the organism. Phase II enzymes catalyze substrate metabolism to more polar products by the conjugation with glucuronic acid, sulfate, glutathione or amino acids, which influences pharmacokinetics and the final biological effects of the metabolized agents (Nagar & Blanchartd, 2006).

Conjugation of uridine-5′-diphospho-α-d-glucuronic acid (UDPGA) with the functional group of aglycone (hydroxyl, amine, carboxyl, sulfhydryl), seems to be crucial among phase II metabolic pathways (Fig. 1). Uridine 5′-diphospho-glucuronosyltransferase isoenzymes (UGTs, originally called UDPGTs) catalyze this type of conjugation, which occurs according to type 2 nucleophilic substitution, SN2, and leads to the formation of β-d-glucuronides. Glucuronides are hydrophilic compounds due to the presence of hydroxyl groups and a dissociated carboxyl group at physiological pH. Thus, they are able to be excreted by active transport systems and eliminated. As a consequence, the first biological function discovered for UGTs was deactivation and detoxification of their substrates. Endogenous UGT substrates are bilirubin, bile acids, lipid acids, steroid and thyroid hormones and lipid soluble vitamins. In this case glucuronidation acts as a control to maintain their appropriate level in the organism in order to avoid physiological disturbances (Bock, 2012, Bock, 2014). The main exogenous UGT substrates are environmental pollutants, carcinogenic compounds and numerous groups of therapeutic agents. Thus, UGT enzymes belong to the family of drug metabolizing enzymes, DME (Rowland et al., 2013).

The superfamily of human UGT proteins is composed of 22 functional isoenzymes, which are classified into four gene families (UGT1, UGT2, UGT3 and UGT8) (Fig. 2) according to sequence similarity (Mackenzie et al., 2005). The enzymes that are most efficient at using UDPGA/UDPGlcUA as the glucosyl donor are the members of UGT1 and UGT2 families. These families are strongly engaged in drug metabolism. Members of the UGT3 family are found primarily in the thymus, testis and kidney, but are undetectable in the liver and gastrointestinal tract. Moreover, the sugar substrates for UGT3 are demonstrated to be UDPGlcNAc (N-acetylated UDPGlcUA) and UDPGal (in which the glucuronic acid of UDPGlcUA is substituted with galactose) instead of UDPGA. Available evidence suggests that this UGT family does not play a significant role in detoxification of xenobiotics (Mackenzie et al., 2011). In turn, the only known member of the UGT8A family, UGT8A1 is an UDP galactose ceramide galactosyltransferase, which uses UDPGal as a cofactor, and similarly has not been observed to participate in drug metabolism (Rowland et al., 2013).

It is well known that the liver has the greatest abundance and array of UGT enzymes (Court et al., 2012). Besides hepatic expression, UGT1A and UGT2B enzymes are present in the kidneys, small intestine, colon, stomach, lungs, epithelium, ovaries, testis, mammary glands and prostate (Court et al., 2012, Ohno and Nakajin, 2009). The most important sites of extrahepatic metabolism are the kidneys and gastrointestinal tract (Knights & Miners, 2010). The majority of members of the UGT1 and UGT2 families are expressed in the human liver, except for UGT1A5, 1A7, 1A8, 1A10 and 2A1. Members of the UGT2B family are more abundant than members of the UGT1A family and UGT2B4 levels in the human liver are the highest of all UGT isoenzymes. Total UGT mRNA expression in the small intestine is estimated as one-seventh of that of adult liver and UGT2B7, 2B17, 1A10 and 1A1 expression is 20%, 19%, 17% and 13%, respectively, of total UGT mRNA in the small intestine. Among different UGT isoforms, UGT1A10 and UGT1A8 are specifically expressed in the intestines, although the expression of UGT1A8 is 22-fold lower than of UGT1A10. Apart from the liver and intestines, high levels of UGT, especially UGT2B15, 2B17 and 1A6 are present in the stomach, whereas UGT2B7, 1A9 and 1A6 are present in the kidney (Court et al., 2012, Oda et al., 2015, Rowland et al., 2013). Little is known of the spatial structure of UGTs. UGT2B7 was the first isoenzyme, for which the crystal structure of the C-terminal end has been proposed (Radominska-Pandya et al., 2010).

There are large differences in UGT expression between different organs and between the same organs in different individuals. UGT expression is modulated by genetic polymorphism (Efferth and Volm, 2005) as well as epigenetic factors, such as DNA methylation or histone acetylation (Guillemette et al., 2010, Oda et al., 2014). UGT regulation by tissue- and ligand-specific transcription factors is also worth considering. Expression of UGTs can be modulated by members of hepatocyte nuclear factor family, HNF1α and HNF4 (Gardner-Stephen and Mackenzie, 2007, Gregory et al., 2003), the caudal homeodomain factor, Cdx2, an intestine specific transcription factor (Gregory et al., 2004, Gregory et al., 2006) and the transcription factor, Forkhead Box A1, a major regulator of the basal and hormone dependent activation of UGT expression (Hu and Mackenzie, 2009, Hu and Mackenzie, 2010). Ligand activated transcription factors include members of nuclear receptor superfamily, such as constitutive androstane receptor, CAR, pregnane X receptor, PXR, farnezoid X receptor, FXR, and liver X receptor, LXR and a member of the bHLH/PAS (basic Helix–Loop–Helix/Per-Arnt-Sim) family, arylhydrocarbon receptor, AhR (Bock, 2010, Bock, 2014).

As mentioned above, the crucial function of UGT enzymes is deactivation of their substrates, both xenobiotics and endobiotics. Deactivation of endogenous substrates plays a role in their clearance and homeostasis, whereas deactivation of xenobiotics, including therapeutics, aims to diminish their toxicity. Glucuronidation of therapeutic agents produces more polar molecules, thereby altering their interactions with biomacromolecules, including lipids of biological membranes and transport proteins. In accordance with this, glucuronides appeared to be better substrates for proteins involved in drug transport compared to the native compounds.

One of the first reports indicating the coordination between export pumps and UGT was published at the beginning of 21th century (Bock et al., 2000). The studies indicated that UGT1A6 and MRP2 expression was coordinately induced by antioxidants, facilitating the excretion of conjugates into the intestinal lumen. However, Burchell and coworkers demonstrated that coexpression of MRP1 and UGT1A1 in V79 cells did not affect the rate of glucuronide export from these cells (Cuff et al., 2001). Subsequent studies indicated that glucuronidation should be considered as a new mechanism of drug resistance (Cummings et al., 2003, Cummings et al., 2004).

The role of multidrug resistance (MDR) in the effectiveness of drug treatments has been identified and widely studied as an element of drug response in antibiotic therapy. Strong evidence for this type of resistance has been also demonstrated in the treatment of epilepsy, certain psychiatric diseases and HIV infection. In most of these disorders UGT-dependent drug resistance has been a quite recent issue. MDR is also one of the major limitations in antitumor therapy. UGTs and drug transporters are indicated to play a co-ordinated role in the antitumor drug response in MDR (Meijerman et al., 2008, Zamek-Gliszczynski et al., 2006). Drug resistance in cancer cells involves three major mechanisms, (i) decrease uptake of water soluble drugs, which requires transporters (ii) changes in cells after drug treatment that affect the capacity of the cytotoxic drug to kill cells and (iii) efflux of the drugs outside the cell by the proteins known as ATP binding cassette (ABC) transporters. The first and second mechanisms are characterized by the broad substrate specificity and abundance of ABC transporter proteins. These may explain the difficulties in circumventing ABC-mediated MDR in vivo in antitumor therapy (Housman et al., 2014, Joyce et al., 2015, Szakács et al., 2006).

MDR transporters can be divided into two classes based on their source of energy: (i) secondary transporters, which use proton gradients to facilitate an antiporter mechanism, and (ii) adenosine triphosphate (ATP) binding cassette (ABC) transporters that couple the hydrolysis of ATP substrate and transport across cell membrane. ABC transporters belong to one of the largest superfamilies of proteins which either import (only in prokaryotes) (Locher, 2009) or export a broad range of substrates that include amino acids, ions, sugars, lipids and drugs (Chang, 2003). These transporters are expressed in tissues important for absorption (e.g. lung and gut) and metabolism and elimination (liver and kidney). In addition, ABC proteins play an important role in maintaining the barrier function of sanctuary site tissues (e.g. blood–brain barrier, blood–cerebral barrier, blood–testis barrier, and the maternal–fetal barrier or placenta). Thus, they have an ability to modulate absorption, distribution, metabolism, excretion and toxicity of xenobiotics (Leslie et al., 2005).

ABC transporters, named after their distinctive ATP-binding cassette domains, are conserved proteins that translocate solutes across cellular membrane. They have a pivotal role in host detoxification and protection of the body against xenobiotics (Szakács et al., 2006). The functional unit of an ABC transporter contains two transmembrane domains (TMDs) and two nucleotide (ATP)-binding domains (NBDs) (Locher, 2009). The NBDs are the motor domains of ABC transporters and consist of a RecA-like subdomain and a helical subdomain. Several conserved sequence motifs are involved in either ATP binding and hydrolysis or in facilitating crucial interfaces in the assembled transporter (Jones & George, 2004). In full transporters, the two NBDs assemble such that these conserved motifs are exposed at the shared interface in a head-to-tail arrangement. In the absence of a nucleotide, there is a gap at the domain interface, with water being able to access the NBD. When ATP is bound, the interface closes and the nucleotides are sandwiched between the NBDs (Chen et al., 2003). The role of the TMD is to recognize and mediate the passage of substrates across the cell membrane (Chang, 2003). There are more than 100 ABC transporters distributed from prokaryotes to humans. Forty-eight ABC genes have been reported in humans (Choi, 2005).

The most typical ABC efflux pump in the cell membrane is MDR1 (P-glycoprotein, PgP), 170 KD protein encoded by the ABCB1 gene. MDR1 was discovered in the early 1970s, and is possibly the best studied ABC drug efflux transporter to date. The MDR1-ABC transporter acts as “hydrophobic vacuum cleaner” because of its ability to remove both lipids and lipophilic drugs through the cell membrane (Kou, 2009).

MDR1 is normally expressed in the transport epithelium of the liver, kidney and gastrointestinal tract, at pharmacological barrier sites, in adult stem cells and in assorted cells of the immune system. It is composed of 12 hydrophobic TMDs and 2 NBDs (Jones and George, 2004, Schmitt and Tampé, 2002). TMDs form a channel for substrate drugs, determine the characteristics of substrates, and efflux substrate drugs whereas NBDs are located in the cytoplasm and participate in ATP binding and hydrolysis. MDR1 undergoes conformational changes upon binding of nucleotide to the NBDs. It has been postulated that intracellular MDR1 substrates first have to insert into the inner hemileaflet of the cell membrane, before being “flipped” to the outer hemileaflet (Schinkel & Jonker, 2003). As most MDR1 substrates are quite hydrophobic, in principle they can diffuse passively across biological membranes at a reasonable rate. Therefore, in the absence of active transport, MDR1 substrates will cross membranes and penetrate into tissues and pharmacological compartments (Schinkel & Jonker, 2003).

The MRP (ABCC) subfamily consists of 12 members including 9 that work as energy-dependent transporters, MRP1–6 (ABCC1–6) and MRP7–9 (ABCC10–12). MRP1 was the first of the family to be identified. MRPs are often further subdivided into short MRPs (MRP4, MRP5, MRP8, MRP9), which contain two membrane-spanning domains and two nucleotide binding domains, and long MRPs (MRP1, MRP2, MRP3, MRP6, MRP7), which contain an additional N-terminal membrane-spanning domain (Deeley et al., 2006). A variety of compounds have been identified as MRP substrates, ranging from traditional DNA damaging cytotoxics (doxorubicin) to antifolates (methotrexate) and microtubule damaging agents (vincristine). The MRP family eliminates a wide range of organic anions and drugs modified by phase II metabolism, including glutathione (GSH), glucuronide and sulfate conjugates, or (in the case of MRP1) can eliminate some drugs in a GSH-dependent manner (Borst et al., 2000, Roundhill et al., 2015). In addition to the role of MRPs in drug resistance, these proteins have also been linked with normal and cancer cell migration in vitro, suggesting a possible secondary role of these proteins in cancer development in addition to traditional efflux activity (Fletcher et al., 2010).

BCRP is a high capacity efflux transporter with wide substrate specificity recognizing molecules of either negative or positive charge, organic anions and sulfate conjugates. It is located in stem cells, some cancer cells and in apical membranes of epithelia involved in drug disposition (Staud & Pavek, 2005). Human ABCG2 encodes a 655 amino acid ABC protein, containing a single N-terminal ATP binding cassette, followed by 6 putative transmembrane segments (TMSs) (Schinkel & Jonker, 2003). The main biological function of BCRP is protection from naturally occurring xenobiotic toxins, similar to MDR1.

Given an essential role that UGTs play in drug resistance, we present here a comprehensive overview of the cooperative impact of glucuronidation and transporter proteins on the final therapeutic effects of a few groups of drug treatments. Analysis of UGT-dependent resistance modulated by drug transport proteins is presented for antiepileptics and psychotherapeutics, as well as for therapeutics against HIV infection, hypertension and hypercholesterolemia. This set of drugs has been widely studied in this respect. More limited is knowledge about immunosuppressants and agents against osteoporosis. The main focus is directed to drug resistance in cancer treatment. We present the differential expression of UGTs in normal and tumor cells, UGTs as a catalyst of drug detoxification as well as mechanisms of intrinsic and acquired resistance toward antitumor therapy. In the end, possible treatments that reverse UGT-mediated resistance are described.

Section snippets

Antiepileptic therapy

Multidrug resistance is a serious obstacle in the treatment of epilepsy, as it is evident in about one-third of cases overall (Sisodiya et al., 2002). Among putative mechanisms explaining drug resistance in epilepsy, the increased removal of antiepileptic drugs (AEDs) from the epileptogenic tissue owing to multidrug transporters has been considered (Schmidt & Löscher, 2005). AEDs, which are lipophilic in general, have to pass the blood–brain barrier (BBB) to reach their molecular targets.

MDR and UGT in schizophrenia

Drug resistance in certain psychiatric diseases, such as schizophrenia, bipolar disorder, depression or anxiety is also connected with the enhanced expression level and polymorphism of proteins responsible for drug glucuronidation and drug transport localized in the BBB. Many studies have shown that several psychotropic drugs used in the treatment of schizophrenia are substrates for MDR1 and ABCB1 gene polymorphisms play a significant role in the therapeutic effects of these drugs (Bozina et

HIV treatment

The use of highly active antiretroviral therapy (HAART) has significantly decreased progression to AIDS and death, changing HIV infection into a chronic disease that requires long-term antiretroviral treatment. However, continuous therapy implies the development of multifactorial drug resistance. On the one hand, the effectiveness of therapy can be affected by viral sensitivity to a drug and, on the other, by drug pharmacokinetics. The second issue strongly contributes to drug metabolism and

Hypertension medications

Increasing evidence has pointed to an involvement of multidrug resistance proteins with hypertension. First of all, ABC transporters are involved in the genesis and maintenance of hypertension. MDR1 was shown to contribute to blood pressure regulation, possibly via the renin–angiotensin system (Delou et al., 2009). It is suggested that variants in expression and polymorphisms of the ABCB1 gene may be involved in resistant hypertension (Lacchini et al., 2014). MRP1, which is responsible for

Immunosuppressants

Drug resistance is also involved in the field of organ transplantation. There is a huge diversity in patients' response to immunosuppressive drugs (IMS) and the development of individual drug therapy is a priority in this field of medicine. The response of individual organ transplant recipients to IMSs differs significantly according to the following factors: disease state, renal and hepatic function, hormonal levels, pharmacokinetic drug–drug interactions, diet, lifestyle and genetic variation

Drugs lowering plasma cholesterol level

UGT-mediated metabolism plays diverse and unique roles in pharmacokinetics of cholesterol lowering drugs. A few groups of chemotherapeutics are used in the treatment of hypercholesterolemia: statins, bile-acid-binding resins, fibrates, cholesterol uptake inhibitors and nicotinic acid (niacin). Usually, hypercholesterolemia is treated by the inhibition of cholesterol synthesis with statins (Knopp, 1999). Expression and polymorphism of UGTs significantly contribute to statin pharmacokinetics.

Osteoporosis therapy

Current therapies for osteoporosis include estrogen-replacement therapy (mestranol), bisphosphonates (alendronate, etidronate, clodronate, ibandronate, pamidronate, risedronate, tiludronate), calcium and vitamin D, calcitonin, sodium fluoride and novel treatments with parathyroid hormone or raloxifene. Raloxifene has mixed estrogen-agonist and estrogen-antagonist activity and is referred to as a selective estrogen-receptor modulator (SERM) (Eastell, 1998). It is suspected that in patients

The relevance of UGTs to drug resistance in cancer treatment

Drug resistance in cancer treatment is a very complex problem and requires extensive research to understand the nature of this process. Early studies elucidated different biochemical mechanisms which may be involved in the development of chemoresistance. Brockman highlighted the following causes of cancer drug resistance: (i) decreased conversion of the therapeutic agent to its active form, (ii) increased degradation of the agent, (iii) increased synthesis of the inhibited target enzyme, (iv)

Concluding remarks

Developing a compound with desirable absorption, distribution, metabolism and excretion (ADME) properties is essential for selecting candidate compounds in drug development. The disruption of at least one element of ADME may result in serious drug resistance. We described here two components of this resistance: UGT-mediated metabolism and ABC protein dependent drug elimination. The first question is how to avoid this type of resistance, considering that UGT isoenzymes are responsible for many

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by grant OPUS 5, 2013/09/B/NZ3/00003 from the National Science Center, Poland.

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