Functional Coupling of ATP-binding Cassette Transporter Abcb6 to Cytochrome P450 Expression and Activity in Liver

Chavan, Hemantkumar; Li, Feng; Tessman, Robert; Mickey, Kristine; Dorko, Kenneth; Schmitt, Timothy M.; Kumer, Sean C.; Gunewardena, Sumedha; Gaikwad, Nilesh W.; Krishnamurthy, Partha

doi:10.1074/jbc.m114.605386

Cited by 9 publications

(9 citation statements)

References 49 publications

(61 reference statements)

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“…One microgram of RNA was used for reverse complementation using the iScript cDNA synthesis kit following the manufacturer's protocol (Bio-Rad, Hercules, CA). Realtime polymerase chain reaction (PCR) was performed with the NAMPT primers sense 59-tccacccaacacaagcaaagt-39 and antisense 59-ttcctctgggaatgacaaagccct-39 using the CFX384TM real-time PCR system (Bio-Rad) (Chavan et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Singh

Haandel

Heruth

et al. 2018

J Pharmacol Exp Ther

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Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis. Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX; however, the mechanism of this interaction has yet to be defined. Therefore, in this study, we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells. Small interfering RNA-based silencing of NAMPT expression resulted in a greater than 3-fold increase in sensitivity to MTX ( < 0.005) that was completely reversed by supplementation with folinic acid. Despite a 68% reduction in cellular NAD levels in NAMPT-deficient cells, no change in expression or activity of dihydrofolate reductase was observed and uptake of MTX was not significantly altered. MTX did not potentiate the depletion of cellular NAD levels, but NAMPT-deficient cells had significant elevations in levels of intermediates of de novo purine biosynthesis and were 4-fold more sensitive to depletion of ATP by MTX ( < 0.005). Supplementation with hypoxanthine and thymidine completely reversed the antiproliferative activity of MTX in NAMPT-deficient cells and corresponded to repletion of the cellular ATP pool without any effect on NAD levels. Together, these findings demonstrate that increased MTX activity with decreased NAMPT expression is dependent on the antifolate activity of MTX and is driven by enhanced sensitivity to the ATP-depleting effects of MTX. For the first time, these findings provide mechanistic details to explain the increase in pharmacological activity of MTX under conditions of reduced NAMPT activity.

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Section: Methodsmentioning

confidence: 99%

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Singh

Haandel

Heruth

et al. 2018

J Pharmacol Exp Ther

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“…It also ensures that toxins are broken down into innocuous compounds to safeguard the organism from harm. For instance, the versatile enzyme cytochrome P450 participates in the metabolic deactivation of thousands of endogenous and exogenous compounds such as bilirubin and drugs, respectively (Chavan et al, 2015 ). Indeed, exposure to noxious metabolites puts the liver at a greater risk of injury and dysfunction than other internal organs.…”

Section: Introductionmentioning

confidence: 99%

Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders

Auger

Alhasawi

Contavadoo

et al. 2015

Front. Cell Dev. Biol.

100

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The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.

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“…Cyp3a11 activity of liver microsomes was determined based on the production of the metabolite 1-hydroxymidazolam from the substrate midazolam ( Chavan et al, 2015 ). In brief, midazolam (5 μM) was incubated at 37°C with hepatic microsomes (0.2 mg/mL) and an NADPH generating system (final volume of 200 μL) for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Altered Function and Expression of ABC Transporters at the Blood–Brain Barrier and Increased Brain Distribution of Phenobarbital in Acute Liver Failure Mice

et al. 2018

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This study investigated alterations in the function and expression of P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the blood–brain barrier (BBB) of acute liver failure (ALF) mice and its clinical significance. ALF mice were developed using intraperitoneal injection of thioacetamide. P-GP, BCRP, and MRP2 functions were determined by measuring the ratios of brain-to-plasma concentration of rhodamine 123, prazosin, and dinitrophenyl-S-glutathione, respectively. The mRNA and proteins expression levels of P-GP, BCRP, and MRP2 were evaluated with quantitative real-time PCR and western blot, respectively. MDCK-MDR1 and HCMEC/D3 cells were used to document the effects of the abnormally altered components in serum of ALF mice on the function and expression of P-GP. The clinical significance of alteration in P-GP function and expression was investigated by determining the distribution of the P-GP substrate phenobarbital (60 mg/kg, intravenous administration) in the brain and loss of righting reflex (LORR) induced by the drug (100 mg/kg). The results showed that ALF significantly downregulated the function and expression of both P-GP and BCRP, but increased the function and expression of MRP2 in the brain of mice. Cell study showed that increased chenodeoxycholic acid may be a reason behind the downregulated P-GP function and expression. Compared with control mice, ALF mice showed a significantly higher brain concentration of phenobarbital and higher brain-to-plasma concentration ratios. In accordance, ALF mice showed a significantly larger duration of LORR and shorter latency time of LORR by phenobarbital, inferring the enhanced pharmacological effect of phenobarbital on the central nervous system (CNS). In conclusion, the function and expression of P-GP and BCRP decreased, while the function and expression of MRP2 increased in the brain of ALF mice. The attenuated function and expression of P-GP at the BBB might enhance phenobarbital distribution in the brain and increase phenobarbital efficacy on the CNS of ALF mice.

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Functional Coupling of ATP-binding Cassette Transporter Abcb6 to Cytochrome P450 Expression and Activity in Liver

Cited by 9 publications

References 49 publications

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders

Altered Function and Expression of ABC Transporters at the Blood–Brain Barrier and Increased Brain Distribution of Phenobarbital in Acute Liver Failure Mice

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