A Novel Xanthine Dehydrogenase Inhibitor (BOF-4272)

Sato, Seiji; Tatsumi, Kunihiko; Nishino, Tokuzo

doi:10.1007/978-1-4899-2638-8_30

Cited by 31 publications

(28 citation statements)

References 3 publications

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“…Since the structure of BOF-4272 resembles that of xanthine, BOF-4272 inhibits the de novo biosynthesis of uric acid by blocking the xanthine oxidase/xanthine dehydrogenase system. 2,3) However, NBMPR, an inhibitor of the plasma membrane equilibrative (Na ＋ -independent, facilitated diŠusion) nucleoside transporter, 16) had no signiˆcant eŠect on the uptake rate of either enantiomer.…”

Section: Resultsmentioning

confidence: 99%

“…[1][2][3][4] BOF-4272 inhibits the de novo biosynthesis of uric acid by blocking the xanthine oxidase/xanthine dehydrogenase system, which catalyzes the last step of purine catabolism. 2,3) The mechanism of inhibition by BOF-4272 was elucidated in an in vitro study using milk xanthine oxidase/xanthine dehydrogenase. 5) BOF-4272 signiˆcantly reduces the concentration of free radicals generated by xanthine oxidase and consequently inhibits cell necrosis.…”

Section: Fig 1 Chemical Structure Of Bof-4272mentioning

confidence: 99%

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Enantioselective Uptake of BOF-4272, a Xanthine Oxidase Inhibitor with a Chiral Sulfoxide, by Isolated Rat Hepatocytes

Naito

Nishimura

2001

YAKUGAKU ZASSHI

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The structures of the S(-) and R(＋) enantiomers of BOF-4272 are shown on the left and right, respectively. The transport mechanisms of the enantiomers of BOF-4272, a new drug for the treatment of hyperuricemia, were studied using freshly prepared rat hepatocytes. BOF-4272 consists of S(-) and R(＋) enantiomers due to a chiral center in the sulfoxide moiety. The uptake of these BOF-4272 enantiomers by hepatocytes was found to be temperature and dose dependent. The temperature-dependent uptake of the S(-) and R(＋) enantiomers showed saturation kinetics. The K m values for the S(-) and R(＋) enantiomers were 59.3 and 25.7 mM, respectively, which was a signiˆcant diŠer-ence (p＜0.05). However, the maximal uptake rate was comparable for both enantiomers. Metabolic inhibitors such as antimycin, oligomycin, rotenone, carbonylcyanide m-chlorophenyl hydrazone, and carbonyl cyanide-p-(tri‰u-romethoxy)-phenylhydrazone signiˆcantly inhibited uptake of the R(＋) enantiomer, but had little eŠect on uptake of the S(-) enantiomer. Ouabain (an inhibitor of Na ＋ /K ＋ -ATPase) and p-nitrobenzylthioinosine (NBMPR, a nucleoside transporter inhibitor) showed no signiˆcant eŠects on the uptake of either enantiomer. Organic anions such as taurocholate and cholate reduced the uptake of both enantiomers. These results suggest that the hepatic uptake of both BOF-4272 enantiomers is not due to simple diŠusion but also involves carrier-mediated uptake. We suggest that the carrier-mediated uptake of BOF-4272 enantiomers includes both NBMPR-insensitive facilitated diŠusion and an active transport system in liver plasma membrane, and that the enantioselective uptake of BOF-4272 is due to diŠerences in a‹nity for the active transporter.

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Section: Resultsmentioning

confidence: 99%

Section: Fig 1 Chemical Structure Of Bof-4272mentioning

confidence: 99%

Enantioselective Uptake of BOF-4272, a Xanthine Oxidase Inhibitor with a Chiral Sulfoxide, by Isolated Rat Hepatocytes

Naito

Nishimura

2001

YAKUGAKU ZASSHI

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“…Although the chemical structure of BOF4272 is similar to that of BOF4249, the K1 values of BOF4272 and BOF4249 for xanthine oxidase were ranged at the order of l0-9 M and l0-5 M, respectively (18). To confirm the specific inhibitory effects of BOF4272 on xanthine oxidase-mediated oxidative changes in hypoperfused liver, either ofthese reagents was added to the perfusate at a final concentration of 10 nM, 20 min before the start of 25% low flow hypoxia in a separate set of experiments.…”

Section: Methodsmentioning

confidence: 95%

Prostaglandin E1 abrogates early reductive stress and zone-specific paradoxical oxidative injury in hypoperfused rat liver.

Suzuki

Suematsu²,

Ishii³

et al. 1994

J. Clin. Invest.

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IntroductionThis study was designed to investigate the effects of prostaglan- Receivedfor publication 10 February 1993 and in revisedform 9 August 1993.Hypoxic liver injury is of major clinical importance in hemorrhagic shock, endotoxemia, metabolic disorders induced by ethanol administration (1, 2), and primary nonfunction in liver transplantation (3). There is a body of evidence showing that mitochondrial damage due to impaired oxygen supply is important as a mechanism of irreversible liver injury. Lemasters et al. ( I ), who examined isolated rat hepatocytes exposed to anoxia-mimicking reagents, has stated that a decrease in mitochondrial inner membrane potential may play a crucial role in bleb formation and subsequent cell death. When the liver is exposed to the prolonged impairment of sinusoidal blood supply, the mitochondrial function of hepatocytes in anoxic pericentral regions should be more easily impaired than in relatively well-oxygenated periportal regions. Accordingly, during low flow hypoxia in which an intralobular gradient of oxygen supply is observed, hepatocytes in the most distal portion of microcirculatory units are expected to show a loss of viability followed by the extension of the damage towards the proximal portion of the lobule.However, the actual time course of the intralobular distribution of cell injury during hypoxia seems quite different. According to Marotto et al. (4), low flow hypoxia-induced cell injury occurs first in the intermediate zone between the periportal and pericentral regions and extends towards the distal portion of hepatic microcirculatory units, producing centrilobular necrosis. Furthermore, our recent observation has revealed that, even under hypoxic condition, the oxidative stress occurs paradoxically in the midzonal region rather than in the anoxic pericentral regions (5). Because of these findings, the relationship between mitochondrial dysfunction and oxygen radical formation in hypoxic liver injury remains unclear.The aim of this study is to investigate the mechanism by which hypoxia-induced mitochondrial dysfunction evokes oxidative cell injury during 25% low flow hypoxia. To that effect, we used dual-color digital microfluorography using two different functional fluorescence probes, rhodamine 123 (Rh 123)' and propidium iodide (PI), which revealed spatial and temporal alterations of mitochondrial function and cell death simultaneously in a hepatic microcirculatory unit ( 1, 6). Furthermore, the temporal and spatial alterations of intrahepatic

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“…[1][2][3][4] Since BOF-4272 contains an asymmetric sulphoxide group (Fig. 1), it exists as R(ϩ) and S(Ϫ) enantiomers.…”

mentioning

confidence: 99%

“…Recently, an asymmetric synthesis of the S(Ϫ) enantiomer of BOF-4272 was reported by Matsugi et al 5) BOF-4272 inhibits the de novo biosynthesis of uric acid by blocking the xanthine oxidase/xanthine dehydrogenase system, which catalyses the last step of purine catabolism. 1,2) The mechanism of the inhibitory action of BOF-4272 was elucidated by an in vitro study using milk xanthine oxidase/xanthine dehydrogenase. 6) BOF-4272 significantly decreases the concentration of free radicals generated by xanthine oxidase and consequently reduces cellular necrosis.…”

mentioning

confidence: 99%

Stereoselective Pharmacokinetics of BOF-4272 Racemate after Oral Administration to Rats and Dogs.

Naito

Nishimura

2002

Biological & Pharmaceutical Bulletin

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The stereoselective pharmacokinetics of BOF-4272 enantiomers in rats and dogs was investigated by simultaneously measuring concentrations in arterial, portal, and venous plasma, the liver, and the kidney at 2 h after the oral administration of the racemic drug. The concentrations of BOF-4272 enantiomers were measured using high-performance liquid chromatography. The concentrations of the S(؊) enantiomer in arterial, portal, and venous plasma were higher than those of the R(؉) enantiomer in rats, but the opposite was found in dogs. In rats, absorption from the intestinal tract into the portal system was almost the same for the two enantiomers, whereas the hepatic uptake of the R(؉) enantiomer was greater than that of the S(؊) enantiomer. In dogs, absorption from the intestinal tract into the portal system was greater for the R(؉) enantiomer than for the S(؊) enantiomer, whereas hepatic uptake was comparable for the two enantiomers. The stereoselectivity of the renal uptake of BOF-4272 enantiomers had little effect on the stereoselectivity of enantiomers in the systemic circulation in both rats and dogs. The stereoselectivity in the systemic circulation of BOF-4272 enantiomers is therefore related to hepatic uptake in rats, and to absorption from the intestinal tract into the portal system in dogs.

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A Novel Xanthine Dehydrogenase Inhibitor (BOF-4272)

Cited by 31 publications

References 3 publications

Enantioselective Uptake of BOF-4272, a Xanthine Oxidase Inhibitor with a Chiral Sulfoxide, by Isolated Rat Hepatocytes

Enantioselective Uptake of BOF-4272, a Xanthine Oxidase Inhibitor with a Chiral Sulfoxide, by Isolated Rat Hepatocytes

Prostaglandin E1 abrogates early reductive stress and zone-specific paradoxical oxidative injury in hypoperfused rat liver.

Stereoselective Pharmacokinetics of BOF-4272 Racemate after Oral Administration to Rats and Dogs.

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