Period1 mediates rhythmic metabolism of toxins by interacting with CYP2E1

Area of Science:

• Chronobiology
• Hepatology
• Toxicology

Background:

• Circadian rhythms regulate liver metabolic functions, including detoxification.
• The precise role of clock genes in responding to and influencing toxin metabolism and toxicity remains largely unknown.

Purpose of the Study:

• To investigate the role of the clock gene Per1 in the liver's response to toxins.
• To elucidate the molecular mechanisms by which Per1 influences toxin metabolism and hepatotoxicity.

Main Methods:

• Utilized a mouse model with Per1 deficiency (Per1-knockout mice).
• Administered toxins such as carbon tetrachloride (CCl4), capsaicin, and acetaminophen to wild-type and Per1-deficient mice.
• Analyzed plasma toxin residues, liver injury markers, fibrosis, and gene/protein expression (PER1, HNF-1α, Cyp2e1).

Main Results:

• Per1 expression was specifically elevated in mice exposed to toxins like CCl4.
• Per1-deficient mice exhibited slower metabolism of CCl4, capsaicin, and acetaminophen, with higher plasma toxin levels.
• Liver injury and fibrosis induced by CCl4 were significantly reduced in Per1-deficient mice.
• PER1 protein binds to HNF-1α, enhancing its recruitment to the Cyp2e1 promoter and increasing Cyp2e1 expression, which promotes toxin metabolism.

Conclusions:

• The clock gene Per1 plays a crucial role in mediating the metabolism of various toxins in the liver.
• Per1 deficiency protects against toxin-induced liver injury and fibrosis by modulating toxin metabolism.
• Targeting Per1 response presents a potential therapeutic strategy for mitigating toxin-induced hepatotoxicity.