Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment

Abstract

1. Hepatic drug-metabolizing activity was investigated in vitro with liver microsomes prepared from rats suffering from hypoxemia with experimentally induced acute lung impairment (ALI).

2. Male Wistar rats received an intrabronchial administration of dilute hydrochloride solution for ALI induction. Pooled liver microsomes were prepared for the normal and ALI rats, and the hepatic drug metabolism mediated by cytochrome P450 (CYP) 3 A was examined in an incubation study with the microsomes.

3. The NADPH-dependent metabolism of midazolam significantly increases in ALI rats as compared with that in normal rats. Testosterone 6β-hydroxylation was also observed to significantly increase in ALI rats.

4. When the hepatic expression of CYP3A proteins was examined, the protein expression of CYP3A1 was shown to significantly increase and that of CYP3A2 remained unaltered in ALI rats. The hepatic expression of NADPH-cytochrome P450 reductase (POR), a protein mediating electron transfer in CYP-mediated drug metabolism, was also revealed to significantly increases in ALI rats.

5. With the findings regarding the midazolam elimination, the hepatic drug-metabolizing activity seems to increase in response to acute hypoxemia, partly due to an altered expression of the CYP3A enzymes, and an augmented electron transfer with an increased POR expression is probably involved in the increase.

Keywords:

• Cytochrome P450
• hypoxemia
• lung impairment
• midazolam
• NADPH-cytochrome P450 reductase

Acknowledgements

This work was partly supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Sciences (15K08097) and by the Advanced Practical Education and Training Program for Leading Pharmacists from Okayama University.

Declaration of interest

The authors declare that there are no conflicts of interest. The authors take full responsibility for any conflict of interest.

Japan Society for the Promotion of Sciences15K08097