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 language | English |
|---|---|
| Journal | Xenobiotica |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2019 |
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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 journal › Article
}
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
C2 - 31403362
AN - SCOPUS:85071313491
JO - Xenobiotica
JF - Xenobiotica
SN - 0049-8254
ER -