Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes.
Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes.
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细胞色素 P450 抑制剂和类固醇激素对小鼠脑微粒体中孕烯醇酮 7-羟基化代谢物形成的影响。
DOI：
10.1677/joe.0.1550343
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
R. Morfin
中科院分区：
文献类型：
--
作者：
J. Doostzadeh;R. Morfin
孕烯醇酮（PREG）在7个α -和7个β -位置的羟基化已经在许多小鼠组织和器官中被报道，相关的细胞色素P450 （CYP）物种有待鉴定。利用薄层色谱和气相色谱-质谱联用技术，我们鉴定了小鼠脑微粒体中产生的7种α -羟基- preg和7种β -羟基- preg代谢物，并对它们的产生进行了动力学研究，7 α -和7 β -羟基化的表观KM值分别为0.5 +/- 0.1微米和5.1 +/- 0.6微米。CYP抑制剂和类固醇激素对PREG 7 α -和7 β -羟基化作用的研究表明：(1)不同的CYP参与了PREG的7 - α -和7 - β -羟基化，因为单独的7 - α -羟基化被甲吡酮、α -萘黄酮、酮康唑和3种β -羟基类固醇广泛抑制；(2)CYP 1A2、2D6、2B1和2B11不参与PREG的7 - α和7 - β -羟基化，因为各自的特异性抑制剂furafylline、奎尼丁和氯霉素没有引起抑制。(3) CYP 1 a1只负责一部分7 beta-hydroxylation怀孕的,因为使用alpha-naphthoflavone,抑制专门CYP 1 a1,没有完全抑制7 beta-hydroxylation,酮康唑,甲吡酮和安替比林,不抑制CYP 1 a1,减少7 beta-hydroxylation的一部分,(iv) 7 alpha-hydroxylation怀孕的可能与其他3 beta-hydroxysteroids如isoandrosterone和共享5-androstene-3β,17 beta-diol强有力的抑制剂,脱氢表雄酮是一种与3-氧类固醇一样弱的非竞争性抑制剂，而(v) 7 β -羟基化不受其他类固醇的显著影响。综上所述，这些发现将用于鉴定负责PREG的7 α -和7 β -羟基化的CYP物种以及研究它们在大脑中的活动。
Hydroxylations of pregnenolone (PREG) at the 7 alpha- and 7 beta-positions have been reported in numerous murine tissues and organs and responsible cytochrome P450 (CYP) species await identification. Using thin layer chromatography and gas chromatography-mass spectrometry, we report identification of 7 alpha-hydroxy-PREG and 7 beta-hydroxy-PREG metabolites produced in mouse brain microsome digests and kinetic studies of their production with apparent KM values of 0.5 +/- 0.1 microM and 5.1 +/- 0.6 microM for 7 alpha- and 7 beta-hydroxylation respectively. Investigation of CYP inhibitors and of steroid hormone effects on both 7 alpha- and 7 beta-hydroxylations of PREG showed that: (i) different CYP were involved in 7 alpha- and 7 beta-hydroxylation of PREG because solely 7 alpha-hydroxylation was extensively inhibited by metyrapone, alpha-naphthoflavone, ketoconazole and 3 beta-hydroxysteroids, (ii) CYP 1A2, 2D6, 2B1 and 2B11 were not responsible for 7 alpha- and 7 beta-hydroxylation of PREG because respective specific inhibitors furafylline, quinidine and chloramphenicol triggered no inhibition, (iii) CYP 1A1 was responsible for only part of the 7 beta-hydroxylation of PREG because use of alpha-naphthoflavone, which inhibits specifically CYP 1A1, did not suppress entirely 7 beta-hydroxylation, while ketoconazole, metyrapone and antipyrine, which do not inhibit CYP 1A1, decreased part of the 7 beta-hydroxylation, (iv) 7 alpha-hydroxylation of PREG may be shared with other 3 beta-hydroxysteroids such as isoandrosterone and 5-androstene-3 beta,17 beta-diol which were strong inhibitors, but not with dehydroepiandrosterone which was a non-competitive inhibitor as weak as 3-oxosteroids, and (v) 7 beta-hydroxylation of PREG was not markedly changed by other steroids. Taken together, these findings will be of use for identification of the CYP species responsible for 7 alpha- and 7 beta-hydroxylation of PREG and for studies of their activities in brain.
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影响因子：
4.1
作者：
KUNZE, KL;TRAGER, WF
通讯作者：
TRAGER, WF
影响因子：
3.8
作者：
J. Halpert;F. Guengerich;J. Bend;M. Correia
通讯作者：
J. Halpert;F. Guengerich;J. Bend;M. Correia
影响因子：
3.9
作者：
CHANG, TKH;GONZALEZ, FJ;WAXMAN, DJ
通讯作者：
WAXMAN, DJ
氯霉素选择性灭活狗肝细胞色素 P-450 的主要苯巴比妥诱导同工酶。
DOI：
--
发表时间：
1987
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Ciaccio,PJ;Duignan,DB;Halpert,JR
通讯作者：
Halpert,JR