Chemico-biological interactionsJun 1, 2019

Daily rhythms in liver metabolism affect hypaconitine toxicity in mice

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Hypaconitine administration in mice showed time-dependent toxicity, being more severe during the light phase.

Toxicity levels of hypaconitine varied based on the time of day, with increased severity observed during the light phase compared to the dark phase.
The observed chronotoxicity was linked to differences in how the body processes hypaconitine at different times of day.
Diurnal expression of the enzyme Cyp3a11, crucial for detoxifying hypaconitine in the liver, influenced its metabolism.
Bmal1 disruption in mice eliminated the daily rhythm of Cyp3a11 expression and the associated time-dependent toxicity of hypaconitine.
Circadian variations in Cyp3a11 activity play a role in the chronotoxic effects of hypaconitine.

Simplified

Hypaconitine is an active and highly toxic constituent derived from Aconitum species. Here we aimed to determine the chronotoxicity of hypaconitine in mice, and to investigate a potential role of metabolism in hypaconitine chronotoxicity. Cardiac toxicity was assessed by measuring CK (creatine kinase) and LDH (lactate dehydrogenase) levels after hypaconitine administration to wild-type and Bmal1(a clock disrupted model) mice at different times of day. The mRNA and protein levels of Cyp3a11 in mouse livers were determined by qPCR and western blotting, respectively. In vitro metabolism was assessed using liver microsomes. Pharmacokinetic study of hypaconitine was performed with wild-type mice. We observed injection time-dependent toxicity (i.e., a more severe toxicity during the light phase than the dark phase) for hypaconitine in mice. The chronotoxicity was attributed to a difference in systemic exposure of hypaconitine caused by time of day-dependent metabolism. Furthermore, circadian metabolism of hypaconitine was accounted for by the diurnal expression of Cyp3a11, a major enzyme for hypaconitine detoxification in the liver. Moreover, Bmal1 ablation in mice abolished the daily rhythm of Cyp3a11 expression and abrogated the time-dependency of hypaconitine toxicity. In conclusion, circadian Cyp3a11 metabolism contributed to chronotoxicity of hypaconitine in mice. This metabolism-based chronotoxicity would facilitate the formulation of best timing for drug administration. -/-

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Daily rhythms in liver metabolism affect hypaconitine toxicity in mice

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