Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure

Masami Doi, Noriko Kajikawa, Tetsuya Aiba

Research output: Contribution to journalArticle

Abstract

The inductive effects of dexamethasone on hepatic midazolam metabolism were examined in Wistar rats with acute renal failure (ARF) to clarify whether the ARF-related decrease in the hepatic expression of drug-metabolizing enzymes is caused by an impairment in the translation/polypeptide formation process. ARF was induced with intramuscular glycerol injection. Dexamethasone was orally administered. Pooled liver microsomes from five rats were prepared with ultracentrifugation for each of four groups, namely, control and ARF rats, control rats with dexamethasone treatment and ARF rats with dexamethasone treatment. Hepatic drug-metabolizing activity was examined in an incubation study with the microsomes, where midazolam was employed as a substrate of cytochrome P450 (CYP) 3A enzymes. The hepatic protein and mRNA expressions of CYP3A23/3A1 and 3A2 enzymes were also evaluated. With dexamethasone treatment, the hepatic metabolic rate of midazolam increased 1.4 times in control rats, while it increased 19.6 times in ARF rats, reflecting the greater induction of hepatic protein expressions of CYP3A enzymes in ARF rats than in control rats. The hepatic protein expression process for CYP3A23/3A1 and 3A2 responds well to dexamethasone treatment in ARF rats, indicating that the translation/polypeptide formation process is not impaired in the presence of ARF.

Original languageEnglish
JournalXenobiotica
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Midazolam
Acute Kidney Injury
Metabolism
Dexamethasone
Rats
Rat control
Liver
Cytochrome P-450 CYP3A
Enzymes
Peptides
Proteins
Pharmaceutical Preparations
Glycerol
Ultracentrifugation
Intramuscular Injections
Liver Microsomes
Therapeutics
Microsomes
Cytochrome P-450 Enzyme System
Wistar Rats

Keywords

  • Acute renal failure
  • CYP3A2
  • dexamethasone
  • hepatic drug metabolism
  • midazolam

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Cite this

Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure. / Doi, Masami; Kajikawa, Noriko; Aiba, Tetsuya.

In: Xenobiotica, 01.01.2019.

Research output: Contribution to journalArticle

@article{6d444bd332614d5fa31419e2db54b51b,
title = "Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure",
abstract = "The inductive effects of dexamethasone on hepatic midazolam metabolism were examined in Wistar rats with acute renal failure (ARF) to clarify whether the ARF-related decrease in the hepatic expression of drug-metabolizing enzymes is caused by an impairment in the translation/polypeptide formation process. ARF was induced with intramuscular glycerol injection. Dexamethasone was orally administered. Pooled liver microsomes from five rats were prepared with ultracentrifugation for each of four groups, namely, control and ARF rats, control rats with dexamethasone treatment and ARF rats with dexamethasone treatment. Hepatic drug-metabolizing activity was examined in an incubation study with the microsomes, where midazolam was employed as a substrate of cytochrome P450 (CYP) 3A enzymes. The hepatic protein and mRNA expressions of CYP3A23/3A1 and 3A2 enzymes were also evaluated. With dexamethasone treatment, the hepatic metabolic rate of midazolam increased 1.4 times in control rats, while it increased 19.6 times in ARF rats, reflecting the greater induction of hepatic protein expressions of CYP3A enzymes in ARF rats than in control rats. The hepatic protein expression process for CYP3A23/3A1 and 3A2 responds well to dexamethasone treatment in ARF rats, indicating that the translation/polypeptide formation process is not impaired in the presence of ARF.",
keywords = "Acute renal failure, CYP3A2, dexamethasone, hepatic drug metabolism, midazolam",
author = "Masami Doi and Noriko Kajikawa and Tetsuya Aiba",
year = "2019",
month = "1",
day = "1",
doi = "10.1080/00498254.2019.1655680",
language = "English",
journal = "Xenobiotica",
issn = "0049-8254",
publisher = "Informa Healthcare",

}

TY - JOUR

T1 - Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure

AU - Doi, Masami

AU - Kajikawa, Noriko

AU - Aiba, Tetsuya

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The inductive effects of dexamethasone on hepatic midazolam metabolism were examined in Wistar rats with acute renal failure (ARF) to clarify whether the ARF-related decrease in the hepatic expression of drug-metabolizing enzymes is caused by an impairment in the translation/polypeptide formation process. ARF was induced with intramuscular glycerol injection. Dexamethasone was orally administered. Pooled liver microsomes from five rats were prepared with ultracentrifugation for each of four groups, namely, control and ARF rats, control rats with dexamethasone treatment and ARF rats with dexamethasone treatment. Hepatic drug-metabolizing activity was examined in an incubation study with the microsomes, where midazolam was employed as a substrate of cytochrome P450 (CYP) 3A enzymes. The hepatic protein and mRNA expressions of CYP3A23/3A1 and 3A2 enzymes were also evaluated. With dexamethasone treatment, the hepatic metabolic rate of midazolam increased 1.4 times in control rats, while it increased 19.6 times in ARF rats, reflecting the greater induction of hepatic protein expressions of CYP3A enzymes in ARF rats than in control rats. The hepatic protein expression process for CYP3A23/3A1 and 3A2 responds well to dexamethasone treatment in ARF rats, indicating that the translation/polypeptide formation process is not impaired in the presence of ARF.

AB - The inductive effects of dexamethasone on hepatic midazolam metabolism were examined in Wistar rats with acute renal failure (ARF) to clarify whether the ARF-related decrease in the hepatic expression of drug-metabolizing enzymes is caused by an impairment in the translation/polypeptide formation process. ARF was induced with intramuscular glycerol injection. Dexamethasone was orally administered. Pooled liver microsomes from five rats were prepared with ultracentrifugation for each of four groups, namely, control and ARF rats, control rats with dexamethasone treatment and ARF rats with dexamethasone treatment. Hepatic drug-metabolizing activity was examined in an incubation study with the microsomes, where midazolam was employed as a substrate of cytochrome P450 (CYP) 3A enzymes. The hepatic protein and mRNA expressions of CYP3A23/3A1 and 3A2 enzymes were also evaluated. With dexamethasone treatment, the hepatic metabolic rate of midazolam increased 1.4 times in control rats, while it increased 19.6 times in ARF rats, reflecting the greater induction of hepatic protein expressions of CYP3A enzymes in ARF rats than in control rats. The hepatic protein expression process for CYP3A23/3A1 and 3A2 responds well to dexamethasone treatment in ARF rats, indicating that the translation/polypeptide formation process is not impaired in the presence of ARF.

KW - Acute renal failure

KW - CYP3A2

KW - dexamethasone

KW - hepatic drug metabolism

KW - midazolam

UR - http://www.scopus.com/inward/record.url?scp=85071313491&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071313491&partnerID=8YFLogxK

U2 - 10.1080/00498254.2019.1655680

DO - 10.1080/00498254.2019.1655680

M3 - Article

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

ER -