The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants in vitro

Abstract

1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C.

2. Compared with that seen at 37 °C, the intrinsic clearance rates (V_max/K_m) of CYP2C9.1 and .2 were decreased (76 ∼ 82%), while that of CYP2C9.3 was unchanged at 34 °C. At 40 °C, CYP2C9.1, .2, and .3 exhibited increased (121%), unchanged and decreased (87%) intrinsic clearance rates, respectively. At 34 °C, the clearance rates of CYP2C19.1A and .10 were decreased (71 ∼ 86%), that of CYP2C19.1B was unchanged, and those of CYP2C19.8 and .23 were increased (130 ∼ 134%). At 40 °C, the clearance rates of CYP2C19.1A, .1B, .10, and .23 remained unaffected, while that of CYP2C19.8 was decreased (74%). At 34 °C, the clearance rates of CYP3A4.1 and .16 were decreased (79 ∼ 84%), those of CYP3A4.2 and .7 were unchanged, and that of CYP3A4.18 was slightly increased (112%). At 40 °C, the clearance rate of CYP3A4.1 remained unaffected, while those of CYP3A4.2, .7, .16, and .18 were decreased (58 ∼ 82%).

3. These findings may be clinically useful for dose optimisation in patients with hypothermia or hyperthermia.

Keywords:

• Cytochrome p450
• genetic polymorphism
• CYP allele
• temperature sensitivity
• body temperature
• hypothermia
• hyperthermia

Acknowledgements

We would like to thank Medical English Service (www.med-english.com) for English language editing.

Authors’ contributions

Participated in the research design: Akiyoshi and Ohtani

Preparation of CYP enzymes: Machida, Cho, Shimoji, Watanabe, Seki, Yamazaki, Guengerich, Nakamura, and Yamamoto

Conducted the experiments: Kojima, Machida, Cho, Akiyoshi, Imaoka, and Ohtani

Performed the data analysis: Kojima, Machida, and Cho

Wrote or contributed to the writing of the manuscript: Kojima, Akiyoshi, and Ohtani

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This study was supported in part by the Japan Research Foundation for JSPS Kakenhi (OH; Grant Number 18K06758) and by the United States National Institutes of Health (FPG; Grant Number R01 GM118122) FP Guengerich was funded by the United States National Institutes of Health (Grant Number R01 GM118122).