Abstract
Although the pyrazolone derivative sulpyrine is widely used as an antipyretic analgesic drug, side effects, including fatal shock, have been reported. However, the molecular mechanism underlying such a severe side effect is largely unclear. Here, we report that the transcription factor CREBH that is highly expressed in the liver plays an important role in fatal shock induced by sulpyrine in mice. CREBH-deficient mice were resistant to experimental fatal sulpyrine shock. We found that sulpyrine-induced expression of cytochrome P450 2B (CYP2B) family genes, which are involved in sulpyrine metabolism, in the liver was severely impaired in CREBH-deficient mice. Moreover, introduction of CYP2B in CREBH-deficient liver restored susceptibility to sulpyrine. Furthermore, ectopic expression of CREBH up-regulated CYP2B10 promoter activity, and in vivo knockdown of CREBH in wild-type mice conferred a significant resistance to fatal sulpyrine shock. These data demonstrate that CREBH is a positive regulator of CYP2B in response to sulpyrine administration, which possibly results in fatal shock.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ampyrone / blood
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Animals
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Aryl Hydrocarbon Hydroxylases / genetics
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Cyclic AMP Response Element-Binding Protein / deficiency
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Cyclic AMP Response Element-Binding Protein / genetics*
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cytochrome P-450 CYP2B1 / genetics
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Cytochrome P-450 CYP2B1 / metabolism
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Cytochrome P450 Family 2
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Dipyrone / adverse effects*
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Dipyrone / pharmacokinetics
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Disease Models, Animal
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Endoplasmic Reticulum Stress / drug effects
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Gene Expression Regulation / drug effects
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Liver / drug effects
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Liver / metabolism
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Male
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Mice
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Mice, Knockout
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Promoter Regions, Genetic
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RNA Interference
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Severity of Illness Index
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Shock / chemically induced*
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Shock / genetics*
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Shock / mortality
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Steroid Hydroxylases / genetics
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Transcriptional Activation
Substances
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Creb3l3 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Ampyrone
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Dipyrone
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Steroid Hydroxylases
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Aryl Hydrocarbon Hydroxylases
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Cyp2b10 protein, mouse
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Cytochrome P-450 CYP2B1
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Cytochrome P450 Family 2
Grants and funding
This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, the Strategic International Cooperative Program (Research Exchange Type), the Japan Science and Technology Agency (JST), and; Kato Memorial Bioscience Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; The Waksman Foundation of Japan INC, Senri Life Science Foundation; The Tokyo Biochemical Research Foundation; The Research Foundation for Microbial Diseases of Osaka University; THE NAKAJIMA FOUNDATION; THE ASAHI GLASS FOUNDATION; The Osaka Foundation for Promotion of Clinical Immunology; The Sumitomo Foundation; The Sagawa Foundation of Promotion of Cancer Research; Suzuken Memorial Foundation; Osaka Cancer Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.