Inhibition studies of dehydroepiandrosterone 7α- and 7β-hydroxylation in mouse liver microsomes
Identifieur interne : 004846 ( Main/Merge ); précédent : 004845; suivant : 004847Inhibition studies of dehydroepiandrosterone 7α- and 7β-hydroxylation in mouse liver microsomes
Auteurs : Jaleh Doostzadeh [France] ; Anne-Cécile Cotillon [France] ; A Da Benalychérif [France] ; Robert Morfin [France]Source :
- Steroids [ 0039-128X ] ; 1998.
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Abstract
Hydroxylations of dehydroepiandrosterone (DHEA) at the 7α- and 7β- positions have been reported in numerous murine tissues and organs, including liver, and the responsible cytochrome P450 (P450) species await identification. Using thin layer chromatography and gas chromatography-mass spectrometry, we report identification of 7α-hydroxy-DHEA and 7β-hydroxy-DHEA metabolites produced in mouse liver microsome digests and kinetic studies of their production with apparent KM values of 3.19 ± 0.292 μM and 2.82 ± 0.241 μM for 7α- and 7β-hydroxylation, respectively. Investigation of P450 inhibitor and of steroid hormone effects on both 7α- and 7β-hydroxylation of DHEA showed that, 1) different P450s were involved in 7α- and 7β-hydroxylation of DHEA because metyrapone inhibited solely 7α-hydroxylation, 2) P450 2D6, 2B1, and 2B11 were not responsible for 7α- and 7β-hydroxylation of DHEA because respective specific inhibitors quinidine and chloramphenicol triggered no inhibition, 3) aside from P450 7b, P450 1A1, and 1A2 may be responsible for a fraction of DHEA 7α- and 7β-hydroxylation because α-naphthoflavone and furafylline, which inhibit specifically P450 1A1 and 1A2, decreased the 7α- and 7β-hydroxylation partly, 4) comparison of these findings with those obtained with brain microsomes suggested that tissue-specific P450 species are responsible for the 7α- and 7β-hydroxylation of DHEA, 5) 7α-hydroxylation of DHEA may be shared with other 3β-hydroxysteroids, such as 3β-hydroxy-5α-androstan-17-one, 5-androstene-3β,17β-diol and pregnenolone, which acted in a noncompetitive manner. Taken together, these findings will be of use for identification of the P450 species responsible for 7α- and 7β-hydroxylation of DHEA and for studies of their activities in liver.
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DOI: 10.1016/S0039-128X(98)00071-3
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xml:lang="en">Hydroxylations of dehydroepiandrosterone (DHEA) at the 7α- and 7β- positions have been reported in numerous murine tissues and organs, including liver, and the responsible cytochrome P450 (P450) species await identification. Using thin layer chromatography and gas chromatography-mass spectrometry, we report identification of 7α-hydroxy-DHEA and 7β-hydroxy-DHEA metabolites produced in mouse liver microsome digests and kinetic studies of their production with apparent KM values of 3.19 ± 0.292 μM and 2.82 ± 0.241 μM for 7α- and 7β-hydroxylation, respectively. Investigation of P450 inhibitor and of steroid hormone effects on both 7α- and 7β-hydroxylation of DHEA showed that, 1) different P450s were involved in 7α- and 7β-hydroxylation of DHEA because metyrapone inhibited solely 7α-hydroxylation, 2) P450 2D6, 2B1, and 2B11 were not responsible for 7α- and 7β-hydroxylation of DHEA because respective specific inhibitors quinidine and chloramphenicol triggered no inhibition, 3) aside from P450 7b, P450 1A1, and 1A2 may be responsible for a fraction of DHEA 7α- and 7β-hydroxylation because α-naphthoflavone and furafylline, which inhibit specifically P450 1A1 and 1A2, decreased the 7α- and 7β-hydroxylation partly, 4) comparison of these findings with those obtained with brain microsomes suggested that tissue-specific P450 species are responsible for the 7α- and 7β-hydroxylation of DHEA, 5) 7α-hydroxylation of DHEA may be shared with other 3β-hydroxysteroids, such as 3β-hydroxy-5α-androstan-17-one, 5-androstene-3β,17β-diol and pregnenolone, which acted in a noncompetitive manner. Taken together, these findings will be of use for identification of the P450 species responsible for 7α- and 7β-hydroxylation of DHEA and for studies of their activities in liver.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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