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.