1. Introduction
Over 40 million individuals worldwide live on plateaus over 2,500 m above sea level. An increasing number of individuals are exposed to high-altitude environments because of the expansion of tourism at these locations. Low oxygen, low pressure, intense radiation, and low temperatures are characteristic of these circumstances. Hypoxia is the main factor affecting human activity. Exposure to high-altitude hypoxia can harm numerous bodily systems, including the respiratory, central neurological, cardiovascular, and endocrine systems. This damage disrupts homeostasis and leads to adaptive, physiological, and metabolic changes. It affects the metabolism of both endogenous substances, such as arachidonic acid (AA), vitamins, and steroids, and exogenous substances, such as drugs and toxins. Maintaining a balance between these substances is crucial for maintaining homeostasis under hypoxic conditions.
Cytochrome P450 (CYP) is the most important family of enzymes involved in metabolizing exogenous and endogenous substances in organisms. CYP expression and activity are regulated by nuclear receptors, epigenetic factors, cytokines, and other factors. Although CYPs are also present in other tissues, including the brain and lungs, they are mostly expressed in the liver and intestine. Exposure to high-altitude hypoxia can have various effects on the lungs, brain, and heart. In severe cases, it may even lead to high-altitude diseases, such as high-altitude pulmonary arterial hypertension, pulmonary edema, and cerebral edema. Studies have demonstrated that hypoxia substantially affects the expression and activity of CYP. Changes in CYP expression lead to alterations in drug pharmacokinetics and changes in CYP levels cause changes in endogenous metabolites. The inhibition of metabolite changes can intervene in the development of high-altitude diseases. Therefore, CYP and its metabolism-generated endogenous metabolites represent a potential mechanism for the development of high-altitude diseases and adaptation of the organism to hypoxia. However, the mechanisms of changes in CYP expression regulated under hypoxia, and how these changes affect drug metabolism and pathophysiology of high-altitude diseases remain unclear. Thus, the objectives of this review were as follows: (1) to summarize and provided updated information on the effects of hypoxia on CYP expression and activity, and outline the current understanding of the mechanisms by which nuclear receptors, epigenetic modifications, cytokines, and gut microbiota regulate CYP under hypoxia; (2) to provide an overview of how these defined changes in CYP regulate drug and endogenous substance metabolism under hypoxia; and (3) to summarize the expression of CYP and its metabolites in high-altitude diseases and explore the possible molecular mechanisms by which they mediate the development of high-altitude diseases.
2. Changes in CYP expression under hypoxia and hypoxia-mediated regulatory mechanisms