title: Ascorbic acid reverses the prolonged anesthetic action of pentobarbital in Akr1a-knockout mice.
abstract: OBJECTIVE
  Aldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, is highly expressed in the liver and is involved in both the detoxification of carbonyl compounds and ascorbic acid biosynthesis. By comparison with wild-type mice, Akr1a-knockout (Akr1a(-/-)) mice and human Akrla-transgenic (Akr1a(tg/+)) mice experience different anesthetic actions from pentobarbital-prolonged in Akr1a-knockout (Akr1a(-/-)) mice and shortened in human Akrla-transgenic (Akr1a(tg/+)) mice.
  
  
  METHODS
  We investigated this alteration in the anesthetic efficacy of pentobarbital in Akr1a genetically modified mice.
  
  
  RESULTS
  Neither the cytosolic protein of wild-type mouse liver nor purified rat AKR1A directly reduced pentobarbital. Ascorbic acid administration neutralized the prolonged duration of the loss of the righting reflex (LORR) in Akr1a(-/-) mice, but preincubation of pentobarbital with ascorbic acid prior to administration did not change the anesthetic effect. Those results indicated that ascorbic acid does not directly reduce pentobarbital. Enzymatic activities and levels of the proteins of some cytochrome P450s that make up a potent detoxification system for pentobarbital showed no changes in the genetically modified mice examined. Thus, ascorbic acid also had no effect on the detoxification system in the liver. The prolonged duration of LORR in the Akr1a(-/-) mice caused by pentobarbital and the neutralization of the anesthetic effect by ascorbic acid together with other results imply that ascorbic acid alters the responses of the neuronal system to anesthetics.
  
  
  CONCLUSIONS
  Pentobarbital action is increased under conditions of ascorbic acid deficiency, and this may have to be taken into account when anesthetizing malnourished patients.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Junitsu
authors.initials: J
authors.lastname: Ito
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Otsuki
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Konno
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kurahashi
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamato
authors.affiliation: Department of Bio-functional Science, Faculty of Pharmacological Science, Kyushu University, Fukuoka, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: Department of Bio-functional Science, Faculty of Pharmacological Science, Kyushu University, Fukuoka, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Internal Medicine, Osaka Koseinenkin Hospital, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan. Electronic address: jfujii@med.id.yamagata-u.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujii
mesh_terms: D000759:Adjuvants, Anesthesia / Q000494:pharmacology*; D000449:Aldehyde Reductase / Q000235:genetics*; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D001206:Ascorbic Acid Deficiency / Q000150:complications; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D057897:Reflex, Righting / Q000187:drug effects; D013997:Time Factors
chemical_list: D000759:Adjuvants, Anesthesia; D000449:Aldehyde Reductase; D010424:Pentobarbital; D001205:Ascorbic Acid
keywords: Aldehyde reductase; Anesthesia; Ascorbic acid; Pentobarbital