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Vol. 28, Issue 3, 315-322, March 2000
Department of Pharmacology, School of Medicine (H.C., M.R.J.) and
Department of Medicinal Chemistry, School of Pharmacy (W.N.H.),
University of Washington, Seattle, Washington
Oxidative conversion of all-trans-retinol
(t-ROH) to all-trans-retinal
(t-RAL) is recognized as the rate-limiting step for biosynthesis of all-trans-retinoic acid from
t-ROH in mammalian hepatic tissues. The purpose of this
study was to investigate the role of human cytochrome P-450
(CYP)-dependent monooxygenation in the conversion of
t-ROH to t-RAL. Adult human liver
microsomes (HLMS) were incubated with t-ROH, and
retinoids generated were identified and quantified by liquid
chromatography-mass spectroscopy, HPLC, and other methods.
HLMS-catalyzed generation of t-RAL from t-ROH was primarily NADPH-dependent and was strongly
inhibited by carbon monoxide. Rates of reactions increased linearly
with time and concentrations of HLMS, and exhibited classical substrate saturation. These observations strongly indicated that the reaction proceeded via CYP-catalyzed monooxygenation. On the basis of responses to selective chemical inhibitors, isoforms from CYP family 1 and the
CYP3A subfamily appeared to be very active. Members of the CYP2C
subfamily and CYP2D6 exhibited lesser activities and CYP2A6, CYP2B6,
and CYP2E1 were virtually inactive. cDNA-expressed human CYP enzymes
(CYP SUPERSOMES) also were used to assess the capacity of individual
CYP enzymes to catalyze the reaction. Based on responses to selective
chemical inhibitors, specific activities, and levels present in adult
human hepatic tissues, CYP1A2 and CYP3A4 strongly appeared to be the
major CYP enzymes catalyzing hepatic oxidative conversion of
t-ROH to t-RAL in the adult human liver.
CYP1A1 and CYP1B1 SUPERSOMES both exhibited exceptionally high
activities, and in extrahepatic tissues, these isoforms could play
important roles in biosynthesis of all-trans-retinoic
acid from t-ROH.
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