Interaction of ethanol oxidation with glucuronidation in isolated hepatocytes

Moldéus, Peter; Andersson, Bo S.; Norling, Anja

doi:10.1016/0006-2952(78)90331-3

Cited by 68 publications

(12 citation statements)

References 19 publications

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“…The inhibitory action of ethanol on glucuronidation in vitro (20) is consistent with the present data obtained in vivo in dogs and humans. However, it is not clear if inhibition of lorazepam conjugation is of the same magnitude as ethanol-induced inhibition of oxidative degradation of diazepam and chlordiazepoxide or other drugs undergoing Type I biotransformation (20,21).…”

Section: LVsupporting

confidence: 94%

“…However, it is not clear if inhibition of lorazepam conjugation is of the same magnitude as ethanol-induced inhibition of oxidative degradation of diazepam and chlordiazepoxide or other drugs undergoing Type I biotransformation (20,21). Comparison between the present data in dogs and data obtained previously in the same group of animals (B), and between the present study of lorazepam and the previous study of chlordiazepoxide (9) and diazepam (22) elimination in man appears in Table 1.…”

Section: LVmentioning

confidence: 99%

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Effect of short-term ethanol administration on lorazepam clearance

et al. 1981

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The disposition of chlordiazepoxide (Librium) and diazepam (Valium), compounds which are initially degraded by oxidative processes, differs from that of oxazepam (Serax) and lorazepam (Ativan, drugs which are inactivated by conjugation with glucuronic acid. Liver disease and cimetidine impair the elimination of the former agents, but not the latter two benzodiazepines. In addition, ethanol inhibits the metabolism of chlordiazepoxide and diazepam. The present studies were performed to determine the effect of short-term ethanol administration on glucuronidation and elimination of lorazepam in dogs and humans. Because, in dogs, lorazepam has a high extraction ratio (approximately 0.9) with an anticipated large presystemic elimination, the influence of ethanol on the presystemic (first-pass) elimination of lorazepam was determined. Administration of p.o. lorazepam to five healthy dogs 1 hr after i.v. saline or ethanol (3 gm/kg) reduced the presystemic elimination of lorazepam by 52% (p less than 0.05). In man, lorazepam has a low (approximately by 0.05) extraction ratio and only a small first-pass effect. Short-term administration of ethanol (0.8 gm/kg followed by 0.5 gm/kg p.o. every 5 hr for four doses) reduced i.v. lorazepam clearance by 18% (p less than 0.03). In dogs and man, ethanol did not significantly alter lorazepam t1/2, plasma protein binding, or distribution volume (Vd beta). The results suggest that short-term ethanol administration impairs the conjugation of lorazepam in dogs and man.

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Section: LVsupporting

confidence: 94%

Section: LVmentioning

confidence: 99%

Effect of short-term ethanol administration on lorazepam clearance

et al. 1981

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“…In the case of synthase, on which the effect was more apparent, maximal activation was reached when the intracellular phenylglucuronide concentration was the most elevated. We have also attempted to modulate the phenylglucuronide concentration with ethanol or galactosamine, both of which inhibit glucuronidation in liver cells (Moldeus et al, 1978;Hanninen and Marniemi, 1970;Ullrich and Bock, 1984). As shown in Table 2, 1OmM ethanol decreased the rate of phenylglucuronide formation by almost 50% and the intracellular concentration of this compound in cells incubated with ['4C]phenol.…”

Section: Relationship Between the Metabolism Of Phenol And Its Effectmentioning

confidence: 99%

“…Furthermore, when the conversion of phenol to phenylglucuronide was slowed down by ethanol or galactosamine, the effects of phenol on synthase and phosphorylase were greatly reduced. Both ethanol and galactosamine inhibit glucuronidation (Moldeus et al, 1978;Hiinninen and Marniemi, 1970;U11-rich and Bock, 1984) by decreasing the concentration of UDP-glucuronate. Ethanol increases the cytosolic concentration of NADH, thereby inhibiting UDP-glucose dehydrogenase (Thurman and Kauffman, 1980;Bodd et al, 1986), and galactosamine traps uridine nucleotides as UDP-galactosamine (Keppler et al, 1970).…”

Section: Nature Of the Compound Responsible For The Effect On Glycogementioning

confidence: 99%

Effect of proglycosyn and other phenolic compounds on glycogen metabolism in isolated hepatocytes

Schaftingen

Hoffmann

1993

European Journal of Biochemistry

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has been investigated. When incubated in the presence of hepatocytes, proglycosyn was metabolized to an 0-demethylated glucuronidated derivative, as determined by fast-atom-bombardment mass spectrometry and enzymic analysis. This metabolite accumulated almost linearly inside the cells to reach a concentration of approximately 3 pmol/g protein after 50 min, without apparent release into the medium. In confirmation of previous work, proglycosyn decreased the level of phosphorylase a and increased that of synthase a in hepatocytes. Washing of cells incubated with proglycosyn for 30 min considerably decreased the concentration of the drug without significantly modifying the intracellular concentration of the metabolite and the activation state of glycogen synthase.Several compounds bearing structural analogy with proglycosyn were also tested for their effect on glycogen metabolism. At millimolar or submillimolar concentrations, resorcinol, m-anisidine, phenol, 3-hydroxyacetophenone, and 3-acetamidophenol, although not 4-acetamidophenol, stimulated the incorporation of ['"C]glucose into glycogen, decreased the level of phosphorylase a and increased the level of synthase a. In the case of phenol, the effect on the glycogen enzymes paralleled the intracellular accumulation of phenylglucuronide. Furthermore, ethanol and D-galactosamine, which decreased the conversion of phenol to phenylglucuronide and the intracellular concentration of phenylglucuronide, counteracted the effect of phenol on the synthase and on the phosphorylase.From these results, it is suggested that the effect of proglycosyn and of simpler phenol derivatives is mediated by glucuronidated metabolites, which act on an intracellular target.

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“…Hepatocellular NADH levels control UDPglucose dehydrogenase activity directly by feedback inhibition. Therefore, the process of UDP-GA generation is affected by carbohydrate metabolism [15], concentration of NAD ϩ , and NADH and NAD ϩ /NADH ratio (redox state) in cytosol [16]. NAD ϩ , and NADH are a closely related oxidation-reduction reaction and affected many metabolisms such as glycolysis, gluconeogenesis, Krebs cycle, and respiratory chain of mitochondria.…”

Section: Figmentioning

confidence: 99%