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PubMedDate not supplied

[Preclinical toxicological study of D-glucuronic acid].

A new D-glucuronic acid (DGA) preparation was studied for toxicological safety on a preclinical level. The results obtained upon a single acute DGA administration in rats, mice, and rabbis showed that the drug exhibits moderate toxicity. A one-month treatment of rats (at a single daily dose of 50, 250, and 500 mg/kg, i.p.) and dogs (50 mg/kg, i.v.) induced neither functional nor morphological changes in hemopoietic and lymphoid organs, kidney, heart, as well as in the digestive, nervous, hemostatic, and fibrinolytic systems. The intraperitoneal administration of DGA produced a pronounced local irritation effects. The liver of both rats and dogs treated with DGA showed dose-dependent adipose degeneration, which decreased upon the drug abolition. The administration of DGA in 50, 100, and 250 mg/kg doses led to dose-dependent changes in some characteristics of the reproductive system in rats. DGA did not modify the extent of allergic reactions and showed no immunotoxicant and mutagen properties.

Animals↗
PubMed1992

Application of 5-azido-UDP-glucose and 5-azido-UDP-glucuronic acid photoaffinity probes for the determination of the active site orientation of microsomal UDP-glucosyltransferases and UDP-glucuronosyltransferases.

A new approach to determining the active site orientation of microsomal glycosyltransferases is presented which utilizes the photoaffinity analogs [32P]5-Azido-UDP-glucose ([32P]5N3UDP-Glc) and [32P]5-Azido-UDP-glucuronic acid ([32P]5N3UDP-GlcA). It was previously shown that both photoprobes could be used to photolabel UDP-glucose:dolichol phosphate glucosyltransferase (Glc-P-Dol synthase), as well as the family of UDP-glucuronosyltransferases in rat liver microsomes. The effects of detergents, proteases, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) on the photolabeling of these enzymes were examined in intact rat liver microsomes. Photolabeling of Glc-P-Dol synthase by either photoprobe was the same in intact or disrupted vesicles, was susceptible to trypsin digestion, and was inhibited by the nonpenetrating inhibitor DIDS. Photolabeling of the UDP-glucuronosyltransferases by [32P]5N3UDP-GlcA was stimulated 1.3-fold in disrupted vesicles as compared to intact vesicles, whereas photolabeling of these enzymes by [32P]5N3UDP-Glc showed a 14-fold increase when vesicles were disrupted. Photolabeled UDP-glucuronosyltransferases were only susceptible to trypsin digestion in disrupted vesicles, and this was further verified by Western blot analyses. The results indicate a cytoplasmic orientation for access of UDP-sugars to Glc-P-Dol synthase and a lumenal orientation of most UDP-glucuronosyltransferases.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2005

[The history of development of glucuronic acid as medicine from 1994 to 1951].

Glucuronic acid (GA) was known to be a detoxifying agent in humans and excereted in urine as a conjugated type. Dr. Morizo Ishidate, Tokyo University, wished to separate GA and determine its metabolic system and role in living organisms. Dr. Tsuyosi Shimozawa studied the metabolic course of GA in rats during the period 1943-1944 under the leadership of Dr. Ishidate. Dr. Ishidate and Dr. Masasi Okada first succeeded in obtaining GA lacton in crystal form from glucose using chemical synthesis in 1950. Dr. Yuji Imai and Mr. Masao Ishihara succeeded to produce GA using a mass-production method in the laboratory of Heiwa Seiyaku Co., Ltd. in 1950. The Ministry of Health and Welfare approved GA as a medicine in 1951.

Animals↗
PubMed1991

Expression and regulation of UDP-glucuronate: neolactotetraosylceramide glucuronyltransferase in the nervous system.

Sulfoglucuronyl glycolipids (SGGLs) are temporally and spatially regulated molecules present in the nervous system during its development. The characteristics of the rat brain enzyme glucuronyltransferase involved in the biosynthesis of SGGLs have been described. The enzyme catalyzes the transfer of glucuronic acid (GlcA) from UDP-GlcA to terminal galactose of the neolacto (type 2) series of glycolipids to form beta 1-3-linked glucuronyl neolacto glycolipids. The enzyme was highly specific for the neolacto series of acceptor glycolipids, neolactotetraosylceramide (nLcOse4Cer), neolactohexaosylceramide (nLcOse6-Cer), and neolactooctaosylceramide (nLcOse8Cer) and was different from the drug-inducible phenol:GlcA transferase. Considerable activity of GlcA transferase was present in the adult rat cerebral cortex, even though SGGLs almost completely disappeared from the cortex by postnatal day 15. In the cerebellum, although levels of SGGLs increased with development, the specific activity of GlcA transferase declined. The results indicated that GlcA transferase was not a regulatory enzyme controlling the expression of SGGLs. Measurements of the levels of nLcOse4Cer and nLcOse6Cer in these neural tissues indicated that the availability of these precursors may regulate the differential expression of SGGLs seen previously. GlcA transferase was significantly reduced in the cerebellar Purkinje cell degenerating murine mutant (pcd/pcd), which is consistent with the loss of SGGLs in the cerebellum of this mutant and specific association of these glycolipids with Purkinje cells.

Animals↗
PubMed1978

[Glucuronic acid, glucuronyltransferase and estrogens in breast cancer and precancer].

The glucuronic acid level in the serum and urine, the diural excretion of estrogens and 17-KS with the urine, the activity of glucuronyltransferase are reported in 101 patients with benign and malignant tumors and in 22 healthy females. The decrease in the activity of glucurolytransferase and increase in the percentage of free (nonconjugated) estrogens in patients with malignant tumors of the mammary gland are noted, the analogous results were obtained in patients with benign tumors, but these are statistically insignificant. The decrease of the glucuronyltransferase activity is suggested to result in the development of relative hyperestrogen in normal total excretion.

17-Ketosteroids↗
PubMed1990

Effect of UDP-glucuronic acid depletion by salicylamide on biliary bilirubin excretion in the rat.

To determine the effect of UDP-glucuronic acid (UDPGA) depletion on bilirubin metabolism, salicylamide (SAM, which is metabolized primarily through glucuronidation, was administered to rats at a dose of 2 mmol/kg, and biliary bilirubin excretion and the proportion of bilirubin glucuronides were determined. At 15 min after administration of SAM, the UDPGA level in the liver was markedly decreased. Although the total biliary excretion of bilirubin showed no change, the bilirubin diglucuronide level in the 0- to 30-min period after SAM administration was significantly lower (36.9 +/- 4.3%) than that of the untreated control group during the same period (47.5 +/- 1.7%; P less than .01). The biliary bilirubin monoglucuronide (BMG) level in the 0- to 30-min period was significantly increased, compared with the control group. The C8-BMG/C12-BMG ratio in the 0- to 30-min period was significantly higher than that of the control group. At 150 min after SAM administration, there was an increase in the UDPGA level in the liver accompanied by an increase in bilirubin diglucuronide and a decrease in BMG. These results indicate that changes in UDPGA in the liver due to SAM administration influence the bilirubin composition of the bile.

Animals↗
PubMed1987

A monoclonal antibody that specifically recognizes a glucuronic acid 2-sulfate-containing determinant in intact chondroitin sulfate chain.

Monoclonal antibodies produced against chick embryo limb bud proteoglycan (PG-M) were selected for their ability to recognize determinants on intact chondroitin sulfate chains. One of these monoclonal antibodies (IgM; designated MO-225) reacts with PG-M, chick embryo cartilage proteoglycans (PG-H, PG-Lb, and PG-Lt), and bovine nasal cartilage proteoglycan, but not with Swarm rat chondrosarcoma proteoglycan. The reactivity of PG-H to MO-225 is not affected by keratanase digestion but is completely abolished after chondroitinase digestion. Competitive binding analyses with various glycosaminoglycan samples indicate that the determinant recognized by MO-225 resides in a D-glucuronic acid 2-sulfate(beta 1----3)N-acetylgalactosamine 6-sulfate disaccharide unit (D-unit) common to antigenic chondroitin sulfates. A tetrasaccharide trisulfate containing D-unit at the reducing end is the smallest chondroitin sulfate fragment that can inhibit the binding of the antibody to PG-H. Decreasing the size of a D-unit-rich chondroitin sulfate by hyaluronidase digestion results in progressive reduction in its inhibitory activity. The results suggest that the epitope has a requirement for a long stretch of a disaccharide-repeating structure for a better fit to the antibody.

Animals↗
PubMedDate not supplied

Quantitation of N-demethylantipyrine in biological samples and isolation and characterization of its glucuronic acid conjugate.

An improved method for quantitating N-demethylantipyrine (N-DEM-AP) in urine by gas chromatography or gas chromatography-mass spectrometry has been developed. Recovery of greater than 90% of N-DEM-AP was achieved by extraction of the sample at pH 1 after addition of 3-amino-1-phenyl-2-pyrazolin-5-one. The coefficient of variation of replicate analyses was 8%. N-DEM-AP was excreted in the urine as a glucuronic acid conjugate. This conjugate was isolated from the urine of an individual receiving antipyrine and purified. The NMR and mass-spectral data are consistent with the conjugate being an O-glucuronide of N-DEM-AP in its enol form.

Antipyrine↗
PubMedDate not supplied

Increased UDP-glucuronosyltransferase activity and UDP-glucuronic acid concentration in the small intestine of butylated hydroxyanisole-treated mice.

Butylated hydroxyanisole (BHA) has been shown to decrease the toxicological and carcinogenic potential of a variety of chemicals. One possible mechanism for chemoprotection is that BHA increases intestinal UDP-glucuronosyltransferase activity and thereby enhances the elimination of the toxicants. Given that oral ingestion is a major route of xenobiotic exposure, we have investigated the actions of BHA on the glucuronidation capacity in the upper small intestine of female mice. Ingestion of high dosages of BHA (600-800 mg/kg/day) for 10 days produced a significant increase in in vitro microsomal acetaminophen glucuronidation but not in diethylstilbestrol conjugation. Furthermore, the concentration of UDP-glucuronic acid, the co-substrate required for glucuronidation reactions, was increased almost 2-fold in small intestine. Ingestion of BHA also increased UDP-glucose concentration and UDP-glucose dehydrogenase activities approximately 2-fold. These findings show that BHA ingestion increases intestinal glucuronidation capacity and suggest that BHA may enhance the intestinal first-pass biotransformation of xenobiotics.

Acetaminophen↗
PubMedDate not supplied

Effect of galactosamine-induced hepatic UDP-glucuronic acid depletion on acetaminophen elimination in rats. Dispositional differences between hepatically and extrahepatically formed glucuronides of acetaminophen and other chemicals.

Galactosamine (GAL) markedly depletes hepatic UDP-glucuronic acid (UDP-GA) whereas extrahepatic UDP-GA is minimally affected. This suggests that GAL predominantly inhibits hepatic glucuronidation. Therefore, the effect of GAL-induced hepatic UDP-GA depletion was examined in bile duct-cannulated rats to determine the role of hepatic glucuronidation in the disposition of acetaminophen (AA). GAL markedly altered the fate of AA-glucuronide but had little or no effect upon other AA metabolites. GAL decreased the biliary excretion of AA-glucuronide up to 92%, whereas reductions in blood levels and urinary excretion of AA-glucuronide did not exceed 50%. This suggests that AA-glucuronide excreted in bile is predominantly of hepatic origin whereas AA-glucuronide found in blood and urine is derived from both hepatic and extrahepatic tissues. Data in the present and previous studies [Gregus, Watkins, Thompson, Klaassen: J. Pharmacol. Exp. Ther. 225, 256, (1983)] indicate that GAL greatly reduced the biliary excretion of AA- and valproic acid-glucuronide whereas the biliary excretion of the glucuronides of phenolphthalein, iopanoic acid, bilirubin, and diethylstilbestrol was only partially decreased. This difference appears to be largely due to differential contributions by the liver and extrahepatic tissues in the glucuronidation of various compounds as well as the availability of glucuronides formed in extrahepatic tissues for biliary excretion. Specifically, the extrahepatically formed glucuronide conjugates of AA and valproic acid are not readily available for biliary excretion whereas the glucuronides of the other compounds are readily excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMedDate not supplied

[Dehydrogenase activity of pentose and glucuronate pathways of glucose utilization in the rat brain during single and repeated cooling].

Repeated supercoolings down to rectal temperatures (19-20 degrees C) results in the different changes in the dehydrogenase activity of pentose and glucuronate pathways in the rat brain: the activity of the pentose cycle oxidative enzymes (glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) lowers considerably and that of VDP-glucose dehydrogenase rises. The dehydrogenase activity in the pentose cycle is found to be inhibited in rats cooled for the first time, the UDP-glucose dehydrogenase activity being preserved at the control level. In the adapted rats the cooling causes mobilization of the pentose cycle, the UDP-glucose dehydrogenase activity remains unchanged.

Adaptation, Physiological↗
PubMed1985

A sulfatase specific for glucuronic acid 2-sulfate residues in glycosaminoglycans.

Although 2-O-sulfated L-iduronic acid (IdoA) residues have been known to occur in heparin, 2-O-sulfated D-glucuronic acid (GlcA) residues have been reported only recently (Bienkowski, M. J., and Conrad, H. E. (1985) J. Biol. Chem. 250, 356-365). Disaccharides prepared by cleavage of heparin and N-deacetylated chondroitin 6-sulfate with nitrous acid were used to demonstrate a new sulfatase that catalyzed the removal of the 2-O-sulfate substituents from GlcA but not IdoA residues. The deamination products were labeled by NaB3H4 reduction to give disaccharides from heparin and chondroitin sulfate which had reducing terminal 2,5-anhydro-D-mannitol ([3H]AManR) and 2,5-anhydro-D-talitol ([3H]ATalR) residues, respectively. IdoA(2-SO4)-[3H]AManR(6-SO4) from heparin and GlcA(2-SO4)-[3H]ATalR(6-SO4) from chondroitin sulfate were purified for use as substrates. GlcA(2-SO4)-[3H]AManR(6-SO4) was prepared by epimerization of IdoA(2-SO4)-[3H]AManR(6-SO4) with hydrazine at 100 degrees C. Lysosomal enzyme preparations from chick embryo chondrocytes and from two normal human fibroblast cell lines catalyzed the removal of the 2-O-SO4 substituent from the uronic acid residues of IdoA(2-SO4)-[3H]AManR(6-SO4), GlcA(2-SO4)-[3H] AManR(6-SO4), and GlcA(2-SO4)-[3H]ATalR(6-SO4). In contrast, a lysosomal enzyme preparation from a human fibroblast cell line deficient in idurono-2-sulfatase (Hunter's-syndrome), which had no activity on the IdoA(2-SO4)-[3H]AManR(6-SO4), converted GlcA(2-SO4)-[3H]AManR(6-SO4) to a mixture of GlcA-[3H] AManR(6-SO4) and [3H]AManR(6-SO4). This enzyme also converted GlcA(2-SO4)-[3H]ATalR(6-SO4) to a mixture of GlcA-[3H]ATalR(6-SO4) and [3H]ATalR(6-SO4). Digestion of both GlcA(2-SO4)-[3H]AManR(6-SO4) and GlcA(2-SO4)-[3H]ATalR(6-SO4) was inhibited by 35SO2-4 and was arrested at the monosulfated disaccharide stage by 1,4-saccharolactone. The glucurono-2-sulfatase exhibited a pH optimum of 4. The results indicate that there exists a separate sulfatase for the removal of sulfate substituents from C-2 of GlcA residues in glycosaminoglycans.

Animals↗
PubMedDate not supplied

[Significance of the ability of Candida Berhout to assimilate D-glucuronic acid, D-glucono-delta-lactone and 5-keto-D-gluconate for systematics].

117 Candida strains representing 76 species and varieties were studied. Most of them readily assimilated glucono-delta-lactone with an exception of species which were imperfect analogues of Pichia spp. with round ascospores, Saccharomyces spp. and Kluyveromyces spp. The test for assimilation of 5-keto-D-gluconate can be used to differentiate varieties of C. guilliermondii, C. pelliculosa, and species C. zeylanoides and C. vinaria. The group of glucuronate-positive species belonging to the genus Candida comprises both ascomycetous and basidiomycetous organisms. The former lack the urease activity. Among the latter, C. curvata, C. humicola, C. marina and C. podzolica produce extracellular polysaccharides identical in the monosaccharide composition to polysaccharides of cryptococci. These four species should be included into the genus Cryptococcus.

Candida↗
PubMed1997

Effects of silymarin on UDP-glucuronic acid and glucuronidation activity in the rat isolated hepatocytes and liver in relation to D-galactosamine toxicity.

Influence of silymarin on UDP-glucuronic acid (UDPGA) and glucuronidation activity of freshly isolated rat hepatocytes in suspension and in rat liver in vivo was examined. Viability of the hepatocytes (> 85%) was not altered in Hank's balanced salt solution at least for 4 hr at 37 degrees C under oxygen. Silymarin at 0.4 mM depleted UDPGA by more than 60% at the end of 4 hr of incubation, the fall in nucleotide pool was rapid and concentration (0.1-0.4 mM)-dependent. The rate of glucuronidation of 3-OH- benzo(a)pyrene (3-OH-BP) determined simultaneously was also reduced significantly; silybin being 3-times more effective than silymarin. Combination of flavonoids with D-galactosamine (GalN) further attenuated the glucuronidation functions of the cells. The flavonoids also offered strong inhibition of UDP-glucose dehydrogenase (UDP-GDH) activity in the liver cytosolic fraction while the activity in hepatocytes was not affected even after 4 hr of incubation. Interestingly, the GalN- induced strong inhibition of UDP-GDH in isolated hepatocytes was completely abolished by flavonoids. Decrease in UDPGA appeared neither due to the activation of UDPGA-pyrophosphatase activity nor to the inhibition of UDP-GDH activity in hepatocytes. Further, the flavonoids also inhibited hepatic UDP-glucuronyltransferase activity towards 3-OH-BP (UGT) both in vitro and in intact cells. On the contrary, silymarin administered (70 mg/kg body wt; i.p.) to rats for 3 hr increased the hepatic UDPGA by 2-fold while GalN (400 mg/kg body wt) reduced the nucleotide content to 50% of control. Coadministration of silymarin and GalN restored the UDPGA content significantly while the activities of UDP-GDH and UGT were comparable to the untreated control. The results indicated that silymarin elicits differential effects on the rate of glucuronidation and contents of UDPGA in the isolated rat hepatocytes and in liver. The flavonoid counteracted D-GalN-induced lowering of UDPGA presumably by relieving UDP-GDH of in vivo inhibition affected by GalN-metabolite.

Animals↗
PubMed1998

Interaction of periodate-oxidized UDP-glucuronic acid with recombinant human liver UDP-glucuronosyltransferase 1A6.

Sodium periodate reacts with UDP-glucuronic acid (UDP-GlcUA) to generate a reactive derivative [periodate-oxidized UDP-GlcUA (o-UDP-GlcUA)]. The ability of this analog of UDP-GlcUA to inactivate and label the human recombinant UDP-glucuronosyltransferase (UGT) UGT1A6 via the UDP-GlcUA binding site was investigated. At an o-UDP-GlcUA concentration of 20 mM, the enzymatic activity of UGT1A6 was totally inactivated after 30 min of incubation at pH 7.4. Inhibition was irreversible, time-dependent, and concentration-dependent and exhibited pseudo-first order kinetics (kinact = 4.0 M-1.min-1). Cosubstrate protection with UDP-GlcUA was biphasic, with no protection in the first phase and almost total protection in the second phase, suggesting that at least 65% of the cross-linking occurs at the cosubstrate binding site. Partial inactivation by o-UDP-GlcUA led to a decrease in Vmax, suggesting that o-UDP-GlcUA can act as an active site-directed inhibitor. Furthermore, proteins, including the UGTs, from membrane fractions of a recombinant V79 cell line expressing the UGT1A6 enzyme and from rat liver microsomes were cross-linked by in situ periodate oxidation of [beta-32P]UDP-GlcUA. The present results suggest that periodate-oxidized UDP-GlcUA, which inactivates UGT1A6 by the possible formation of a Schiff base adduct with active site lysyl residues, can be used as a new affinity label for the UDP-GlcUA binding site.

Animals↗
PubMed1995

Biochemical modulation of iododeoxyuridine by N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[cd]indole glucuronate (AG-331) leading to enhanced cytotoxicity.

Inhibition of thymidylate synthase (TS) may increase incorporation of thymidine analogues into DNA, leading to increased inhibition of colony formation in tumor cells. We have reported previously that TS inhibition by N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6,-ylmethyl)-N -methylamino]-2 - thenoyl)-L-glutamic acid (ICI D1694 or Tomudex), a folate-based TS inhibitor, increases the cytotoxicity of iododeoxyuridine (IdUrd), a thymidine analogue, in MGH-U1 human bladder and HCT-8 human colon cancer cells. N6-[4-(Morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]-indole glucuronate (AG-331) differs from ICI D1694 in that it is a de novo designed lipophilic TS inhibitor, it does not require a specific carrier for cellular uptake, and it does not undergo intracellular polyglutamation. Exposure of MGH-U1 cells to 5 microM AG-331 for 24 hr decreased clonogenic survival by 30%, but almost completely inhibited TS activity. IdUrd is a cytotoxic thymidine analogue, with IC50 and IC90 values after 24-hr exposures in MGH-U1 cells of 13 and 81 microM, respectively. The combination of IdUrd and AG-331 resulted in an enhanced antitumor effect, as compared with the effect of either agent alone. The cytotoxic IC50 of IdUrd decreased from 13 to 1.5 microM, and the IC90 decreased from 81 to 5 microM with the addition of 5 microM AG-331. Biochemical studies of the combination revealed that pretreating MGH-U1 cells with 5 microM AG-331 increased IdUrd incorporation into cellular DNA by 3.8-fold. This increased incorporation was associated with a greater proportion of DNA single-strand breaks than observed with either agent alone, and the combination of 5 microM AG-331 plus IdUrd produced up to a 2.5-fold increase in DNA single-strand breaks as compared with IdUrd alone. The effects of AG-331, IdUrd, and the combination of IdUrd and AG-331 on the colony-forming ability of normal human bone marrow CFU-GM cells was determined as a measure of myelosuppression. The combination of IdUrd and AG-331, at the same concentrations as those used in the MGH-U1 cells, produced a wider therapeutic index relative to that of IdUrd alone, and the therapeutic index for the combination was 6.5, as compared with 4.0 for IdUrd plus ICI D1694 in previous studies from this laboratory. These observations suggest that the combination of IdUrd and AG-331 may enhance antitumor effects with minimal myelosuppression in vivo.

Antimetabolites, Antineoplastic↗
PubMed1988

Conventional and laser induced fluorescence detection of glucuronic acid conjugates after derivatization and liquid chromatographic separation.

Pre-chromatographic derivatisation of the carboxylic acid function of glucuronic acid conjugates is a suitable method for the selective and ultra-sensitive analysis of these compounds in urine and plasma samples. This goal is achieved by applying an indirect derivatisation procedure and laser induced fluorescence detection with a homemade detection system equipped with a continuous-wave argon-ion laser. The minimum detectable amounts for the analytes, after derivatisation, are about 3 amol using the fluorescein fluorophore. In comparison with conventional induced fluorescence detection a gain in sensitivity of over four orders of magnitude is obtained.

Journal Article↗
PubMed2005

MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (beta-D-glucuronate).

Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette transporter that confers multidrug resistance on tumor cells. Much convincing evidence has accumulated that MRP1 transports most substances in a GSH-dependent manner. On the other hand, several reports have revealed that MRP1 can transport some substrates independently of GSH; however, the importance of GSH-independent transport activity is not well established and the mechanistic differences between GSH-dependent and -independent transport by MRP1 are unclear. We previously demonstrated that the amino acids W261 and K267 in the L0 region of MRP1 were important for leukotriene C4 (LTC4) transport activity of MRP1 and for GSH-dependent photolabeling of MRP1 with azidophenyl agosterol-A (azidoAG-A). In this paper, we further tested the effect of W222L, W223L and R230A mutations in MRP1, designated dmL0MRP1, on MRP1 transport activity. SN-38 is an active metabolic form of CPT-11 that is one of the most promising anti-cancer drugs. Membrane vesicles prepared from cells expressing dmL0MRP1 could transport SN-38, but not LTC4 or estradiol-17 (beta-D-glucuronate), and could not be photolabeled with azidoAG-A. These data suggested that SN-38 was transported by a different mechanism than that of GSH-dependent transport. Understanding the GSH-independent transport mechanism of MRP1, and identification of drugs that are transported by this mechanism, will be critical for combating MRP1-mediated drug resistance. We performed a pairwise comparison of compounds that are transported by MRP1 in a GSH-dependent or -independent manner. These data indicated that it may be possible to predict compounds that are transported by MRP1 in a GSH-independent manner.

Base Sequence↗