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