The Effects of Drugs on CYP3A Enzyme Activity and Protein Expression Through Ubiquitination Modification Regulation

Cytochrome P450 3A4 (CYP3A4) is one of the most important members of the cytochrome P450 subfamily, which is involved in the catalytic process of many drug activation or deactivation. Meanwhile, it is also a risk factor for drug-induced toxic reactions. Our research investigates the impact of drugs on CYP3A4 enzyme activity and protein expression, and that CYP3A4 inhibition induced by drugs may exacerbate under hypoxia. Molecular docking has found that the drug has binding sites with amino acid residues in the active region of CYP3A4, which may affect the ability of the CYP3A4 enzyme to metabolize drugs. Twenty male Sprague Dawley rats were divided into two groups: control (FiO₂: 21%), hypoxia (FiO₂: 10%) for 14 days. Liver microsomes from hypoxic and normoxic rats were used for in vitro experiments by high-performance liquid chromatography. Drug concentration in blood in vivo was measured by LC–MS/MS. Further studies have revealed that drugs mediate the degradation of CYP3A4 ubiquitination-proteasome pathway through E3 ubiquitin ligase gp78 by immunoprecipitation, which may exacerbate the CYP3A4 inhibition under hypoxic conditions. These elucidated that the inhibition of CYP3A4 may worsen under pathological conditions (such as hypoxia), providing a basis for rational clinical medication to reduce or avoid drug interactions and toxic reactions.