(R)- and (S)-Verapamil Differentially Modulate the Multidrug-resistant Protein MRP1

Perrotton, Thomas; Trompier, Doriane; Chang, Xiu Bao; Pietro, Attilio Di; Baubichon‐Cortay, Hélène

doi:10.1074/jbc.m703964200

Cited by 60 publications

(58 citation statements)

References 31 publications

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“…In the presence of the widely used ABCB1 inhibitor verapamil, the maternofetal talinolol permeability was significantly increased, even to a higher extent than in the presence of probenecid, although the specific modulator PSC833 lacked marked influence (Naito and Tsuruo, 1989). R-Verapamil is also known to modulate ABCC1 and OATP as confirmed for the uptake of fexofenadine (Cvetkovic et al, 1999;Perrotton et al, 2007). ABCC1 seems to be localized to the basal and brush-border membrane of the syncytiotrophoblast and to the blood vessel endothelia, and it undergoes gestational maturation.…”

Section: Permeability Of Antipyrine and Creatinine And Viability Charmentioning

confidence: 99%

Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta

May¹,

Minaříková²,

Linnemann³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Placental syncytiotrophoblasts are known to express the efflux transporter proteins P-glycoprotein (ABCB1) and multidrug resistance-associated protein 2 (ABCC2), which are supposed to be a functional part of the human placental barrier. With advancing gestational age, expression of ABCB1 decreases progressively, whereas ABCC2 is more expressed. To evaluate to which extent they contribute to placental barrier function at term, permeability of talinolol, a substrate of both carriers, was measured using a validated human placenta perfusion model. We identified in randomized, crossover experiments a unidirectional transfer of talinolol in the fetomaternal direction because the maternofetal trans- The human placenta brings the maternal and fetal blood circulations closely together, separated only by the single cell layer of the syncytiotrophoblast. It regulates the supply of nutrients and gases, the elimination of fetal waste products, and the exposure to exogenous substances, including drugs. There is growing evidence that energydependent transporter processes are involved in the maternofetal exchange of endogenous and xenobiotic substances. Meanwhile, more than 30 transport proteins were identified that are expressed to the maternal-facing brush-border apical membrane or to the fetal-facing basolateral membrane of the syncytiotrophoblast (Marzolini and Kim, 2005;Evseenko et al., 2006;Myllynen et al., 2007). There is evidence for some of them to be significantly involved in drug disposition, such as the maternal-facing efflux carriers P-glycoprotein (ABCB1) and the multidrug resistance-associated protein 2 (ABCC2), a second member of the ABC transporter family (St. Pierre et al., 2000;Marzolini and Kim, 2005;Ceckova-Novotna et al., 2006;Evseenko et al., 2006). ABCB1 and ABCC2 share a wide overlapping substrate spectrum and may be coregulated, e.g., in the small intestine Jedlitschky et al., 2006). Information on their function in the human placenta, however, is contradictory and limited so far to ABCB1. Because placental ABCB1 expression decreases with advancing gestation age whereas ABCC2 undergoes gestational maturation, we hypothesized that ABCC2 in term placentas may be more important than ABCB1 for the transfer of drugs that are substrates of both carriers (Meyer zu Schwabedissen et al., 2005;Sun et al., 2006). A suitable probe drug to evaluate function of ABCB1 and ABCC2 in humans is the nonmetabolized ␤ 1 -selective blocker talinolol, which is a high affinity substrate of ABCB1 as evidenced by in vitro experiments and pharmacokinetic studies in humans and of ABCC2 as concluded from major changes in disposition in Abcc2-deficient GY/ TR Ϫ rats (Spahn-Langguth et al., 1998;Gramatté and Oertel, 1999;Westphal et al., 2000;Bernsdorf et al., 2003). ␤ 1 -Selective blockers are used in the treatment of hypertension during pregnancy (Magee et al., 2000).We provide evidence from perfusion experiments using the dually perfused human placenta model that the placenta serves as a functional barrier for talinolol a...

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Section: Permeability Of Antipyrine and Creatinine And Viability Charmentioning

confidence: 99%

Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta

May¹,

Minaříková²,

Linnemann³

et al. 2008

Drug Metab Dispos

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“…Pharmacological activation of MRPs induces apoptosis by GSH depletion (139,197,232,235). However, contradictory results have been reported regarding the role of MRP1 in GSH efflux during apoptosis.…”

mentioning

confidence: 99%

Glutathione Efflux and Cell Death

Franco

Cidlowski

2012

Antioxidants & Redox Signaling

200

128

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Significance: Glutathione (GSH) depletion is a central signaling event that regulates the activation of cell death pathways. GSH depletion is often taken as a marker of oxidative stress and thus, as a consequence of its antioxidant properties scavenging reactive species of both oxygen and nitrogen (ROS/RNS). Recent Advances: There is increasing evidence demonstrating that GSH loss is an active phenomenon regulating the redox signaling events modulating cell death activation and progression. Critical Issues: In this work, we review the role of GSH depletion by its efflux, as an important event regulating alterations in the cellular redox balance during cell death independent from oxidative stress and ROS/RNS formation. We discuss the mechanisms involved in GSH efflux during cell death progression and the redox signaling events by which GSH depletion regulates the activation of the cell death machinery. Future Directions: The evidence summarized here clearly places GSH transport as a central mechanism mediating redox signaling during cell death progression. Future studies should be directed toward identifying the molecular identity of GSH transporters mediating GSH extrusion during cell death, and addressing the lack of sensitive approaches to quantify GSH efflux.

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“…It has been shown that intestinal ABCB1 expression was increased by spironolactone, 73 an aldosterone antagonist widely used to treat patients with congestive heart failure, leading to a diminished absorption of digoxin, which is transported by ABCB1 in the intestine and liver. 74 On the other hand, verapamil, an inhibitor of both ABCB1 75 and ABCC1, 76 was shown to increase plasma digoxin concentration attributed to inhibition of ABCB1 activity, resulting in a decreased renal tubular elimination of digoxin. 77 Also, the toxicity of the interaction between quinidine and digoxin was shown to be attributed to the inhibition of ABCB1.…”

Section: Treatment Of Hypertension: the Role Of Mdr Proteins In Drug mentioning

confidence: 99%

Unveiling the Role of Multidrug Resistance Proteins in Hypertension

2009

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H ypertension is a chronic condition associated with an increased risk of mortality and morbidity. It is estimated to cause 4.5% of current global disease burden, and its prevalence is similar in both developing and developed countries. 1 According to a recent review, Ϸ54% of stroke, 47% of ischemic heart disease, 75% of hypertensive disease, and 25% of other cardiovascular disease worldwide can be attributable to high blood pressure. 2 Altered levels of angiotensin and aldosterone are common findings in hypertension. Aldosterone has been shown to play an important role in the pathophysiology of numerous cardiovascular disorders, including heart failure and hypertension, 3 and the renin-angiotensin-aldosterone system is currently an important target for 5 antihypertensive drug classes: ␤-blockers, renin inhibitors, angiotensin-conversion enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists. 4 In the last few years, increasing evidence has pointed to an involvement of multidrug resistance (MDR)-related proteins with hypertension. Both ABCB1 (P-glycoprotein) and ABCC1 (MDR-associated protein 1), the 2 main proteins first described in multidrug-resistant tumors, are known to physiologically transport several endobiotics, including hormones. 5,6 Moreover, ABCB1 and ABCG2 (the third protein related to MDR), seem to also be related to the secretion of several drugs to urine, including some antihypertensives. 7,8 This review summarizes the recent findings regarding the relationship between MDR-related proteins and hypertension. ABC Superfamily and MDR in CancerMDR is still the main cause of failure in cancer chemotherapy. Although it is a multifactorial phenomenon, virtually all MDR cells present an ATP-dependent reduction in intracellular drug accumulation because of the overexpression of Ն1 of 3 proteins belonging to the ATP-binding cassette (ABC) family of transporters. 9,10 The ABC superfamily is one of the largest protein families, and its members have been found in virtually all organisms examined up to now. It is consisted of 7 subfamilies, ABCA, ABCB, ABCC, ABCD, ABCE, ABCF, and ABCG, in which each protein receives a number, eg, ABCA1, ABCC7, or ABCG2. The majority of the ABC proteins are membrane transporters that actively translocate a wide range of substrates to various cellular compartments using ATP hydrolysis, which may explain the many functions fulfilled by these proteins in different organisms.The first ABC protein related to MDR was initially named P-glycoprotein and subsequently MDR1, with P being a reference for an apparent altered membrane permeability conferred by its overexpression. 11 This protein is now called ABCB1, meaning that it is the first member of the B subgroup of the ABC superfamily. The second MDR-related protein was discovered 16 years later and was called MDRassociated protein, 12 or MDR-associated protein 1, and is now renamed ABCC1. The third important MDR-related protein, now called ABCG2, was discovered almost simultaneously by 3 distinct groups, receiv...

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(R)- and (S)-Verapamil Differentially Modulate the Multidrug-resistant Protein MRP1

Cited by 60 publications

References 31 publications

Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta

Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta

Glutathione Efflux and Cell Death

Unveiling the Role of Multidrug Resistance Proteins in Hypertension

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