Evaluation of Circadian Rhythm Disturbances in Mice Models with Impaired Heme Biosynthesis Induced by Environmental Chemicals

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We have developed a mouse model of hepatic porphyria induced by ingestion of a chemical substance, griseofulvin (GF), and analyzed the characterization of biochemical and behavioral phenotypes of the porphyria model mice. The porphyria mice exhibited tremendous accumulation of aminolevurinic acid (ALA) and porphyrins asn heme precursors, and also had symptoms, such as liver injury and skin inflammation. In addition, they exhibited several neurological and psychological behaviors, such as anxiety and depression, typically observed in acute porphyria. Moreover, we found that these mice had differential sensitivities to psychological drugs, such as diazepam, comparing to the control mice, without any difference in the pharmacokinetics. Furthermore, circadian activity and temperature rhythms of these mice exhibited phase-advances by a few hours. The abnormal circadian rhythms were ameliorated by the treatment of heme. In conclusion, we demonstrated heme-regulated abnormality of circadian rhythms in the mice model of hepatic porphyria induced by GF.