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The effect of fluroxene [(2,2,2-trifluoroethoxy)ethane] on haem biosynthesis and degradation.

Abstract
Acute fluroxene treatment of male Wistar rats decreases the amounts of hepatic microsomal cytochrome P-450 and haem, increases the activities of hepatic delta-aminolaevulinate synthase and haem oxygenase, and increases the amounts of haem precursors (delta-aminolaevulinate and porphobilinogen) in the urine. All of the above effects of fluroxene are enhanced by pretreatment of the experimental animals with 3-methylcholanthrene and phenobarbital. The amounts of porphyrins in the urine and faeces were generally unaffected by acute fluroxene treatment of uninduced or 3-methylcholanthrene- or phenobarbital-induced Wistar rats. 2,2,2-Trifluoroethyl ethyl ether, the saturated analogue of fluroxene, did not affect the amounts of hepatic cytochrome P-450 and haem, the amounts of any of the haem precursors in the urine or faeces, or the activity of hepatic haem oxygenase in phenobarbital-induced male Wistar rats. The amounts of hepatic cytochrome P-450 and haem and of the haem precursors in urine and faeces, and the activity of delta-aminolaevulinate synthase, were generally not altered by acute fluroxene treatment of uninduced male Long-Evans rats. Chronic treatment of Wistar rats with fluroxene resulted in small increases in the amounts of delta-aminolaevulinate and porphyrins in urine. The amounts of porphobilinogen in urine were elevated up to 2000%, whereas the amounts of the porphyrins in faeces were generally unaffected. After chronic fluroxene treatment, the activity of delta-aminolaevulinate synthase was increased, whereas the activity of uroporphyrinogen synthase was decreased. It is concluded that acute fluroxene treatment may affect haem biosynthesis and degradation by a mechanism similar to allylisopropylacetamide, namely by stimulating an atypical cytochrome P-450-dependent pathway for haem degradation. The effects of chronic fluroxene treatment on haem biosynthesis may be a consequence of this mechanism or a result of the inhibition by fluroxene of uroporphyrinogen synthase. Chronic fluroxene treatment of male rats affects the haem biosynthetic pathway in a manner similar to that seen in human genetic acute intermittent porphyria.
AuthorsM R Ziman, J J Bradshaw, K M Ivanetich
JournalThe Biochemical journal (Biochem J) Vol. 190 Issue 3 Pg. 571-80 (Sep 15 1980) ISSN: 0264-6021 [Print] England
PMID6110422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Ethers
  • Porphyrins
  • Heme
  • Cytochrome P-450 Enzyme System
  • 5-Aminolevulinate Synthetase
Topics
  • 5-Aminolevulinate Synthetase (metabolism)
  • Animals
  • Cytochrome P-450 Enzyme System (metabolism)
  • Ethers (pharmacology)
  • Feces (analysis)
  • Heme (biosynthesis, metabolism)
  • Liver (drug effects, metabolism)
  • Male
  • Microsomes, Liver (drug effects, metabolism)
  • Porphyrins (urine)
  • Rats

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