Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A resistant descendant of the human stomach carcinoma cell line EPG85-257 was selected in the presence of increasing concentrations of daunorubicin (DRC). To avoid the expression and activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), cells were cultured in the presence of verapamil. The resulting cells were used to evaluate an induced carbonyl reduction as a new determinant in DRC resistance. The MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide) toxicity assay was performed to estimate sensitivity to DRC in both cell lines. IC50 values of DRC increased almost 8-fold in the resistant descendants compared to the parental cell line. P-gp transcripts were detectable in both cell lines at only very low levels, and no significant alterations between sensitive and resistant cells were observed. MRP mRNA expression was markedly higher compared to P-gp mRNA, but, as was the case with P-gp, MRP mRNA levels in sensitive and resistant cells showed no alteration. This was probably due to the effect of the presence of verapamil during cell selection. Another known drug resistance factor, the lung resistance-related protein (LRP), was not at all detectable. Interestingly, resistant cells possessed 6-fold higher levels of DRC carbonyl-reducing activity, leading to the less toxic 13-hydroxy metabolite daunorubicinol (DRCOL). The 6-fold higher DRCOL formation roughly parallels the 8-fold increase in DRC IC50 values during cell selection, and therefore may account for DRC resistance in these cells. The determination of specific carbonyl reducing enzymes, known to be involved in DRC detoxification, revealed that mRNA expression of carbonyl reductase (EC 1.1.1.184), aldose reductase (EC 1.1.1.21), and dihydrodiol dehydrogenase 2 (EC 1.3.1.20) increased in the resistant descendant. In contrast, the phase II-conjugating enzyme activities of glutathione S-transferases were significantly lower in resistant than in sensitive cells, whereas those of glucuronosyl transferase were not detectable in either cell line. Apparently, conjugating enzymes are not involved in DRC resistance in human stomach carcinoma cells. These studies indicate that DRC resistance in human stomach carcinoma cells may appear as a result of an induction of metabolic DRC inactivation via carbonyl reduction to the less active 13-hydroxy metabolite DRCOL.
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PMID:Development of daunorubicin resistance in tumour cells by induction of carbonyl reduction. 1060 58

Since the severe cardiotoxicity of anthracyclines has been attributed to the intramyocardial formation of C-13 alcohol metabolites, the kinetics of cardiac metabolite formation and disposition as well as the effect of carbonyl reductase inhibitors are of specific interest. This study was designed to investigate the effect of rutin and phenobarbital on the pharmacokinetics of idarubicin (IDA) and its conversion to idarubicinol (IDOL) in the single-pass perfused rat heart. After infusion of IDA (0.5 mg) during 1min, the venous outflow concentrations of IDA and IDOL were measured up to 80 min in the presence and absence of rutin and phenobarbital. A kinetic model was developed to help to interpret the concentration profiles in terms of compartmentation of IDOL formation and to estimate parameters quantitatively descriptive of the transport and biotransformation processes. Rutin and phenobarbital significantly reduced the residual amount of IDOL in heart to 64 and 47% of control, respectively. Pharmacokinetic modeling of the data revealed that IDOL is generated in two different compartments, besides the tissue compartment characterized by saturable uptake, also the compartment that accounts for the quasi-instantaneous initial distribution process is involved. The efflux rate constant of IDOL, k(21,IDOL,) was much smaller than that of IDA. Rutin and phenobarbital significantly reduced IDOL production. Additionally, phenobarbital competitively inhibited the saturable uptake of both IDA and IDOL (increase in apparent Michaelis constants). Reanalysis of data obtained in previous experiments showed that P-glycoprotein inhibitors (verapamil and amiodarone) reduced IDOL uptake in a similar way as already shown for IDA. The present study further supports the utility of pharmacokinetic modeling in identifying sites of drug interactions within the heart.
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PMID:Modeling the metabolism of idarubicin to idarubicinol in rat heart: effect of rutin and phenobarbital. 1264 73