title: CREBH determines the severity of sulpyrine-induced fatal shock.
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.
authors: Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors: Naganori
authors: N
authors: Kamiyama
authors: Masahiro
authors: M
authors: Yamamoto
authors: Hiroyuki
authors: H
authors: Saiga
authors: Ji Su
authors: JS
authors: Ma
authors: Jun
authors: J
authors: Ohshima
authors: Sakaaki
authors: S
authors: Machimura
authors: Miwa
authors: M
authors: Sasai
authors: Taishi
authors: T
authors: Kimura
authors: Yoshiyasu
authors: Y
authors: Ueda
authors: Hisako
authors: H
authors: Kayama
authors: Kiyoshi
authors: K
authors: Takeda
mesh_terms: D000675:Ampyrone / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004177:Dipyrone / Q000009:adverse effects* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012720:Severity of Illness Index; D012769:Shock / Q000139:chemically induced* / Q000235:genetics* / Q000401:mortality; D013250:Steroid Hydroxylases / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000675:Ampyrone; D004177:Dipyrone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D019362:Cytochrome P-450 CYP2B1; D000072467:Cytochrome P450 Family 2