2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits steroidogenesis in the rat testis by inhibiting the mobilization of cholesterol to cytochrome P450scc.
2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits steroidogenesis in the rat testis by inhibiting the mobilization of cholesterol to cytochrome P450scc.
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2,3,7,8-四氯二苯并-p-二恶英通过抑制胆固醇向细胞色素 P450scc 的动员来抑制大鼠睾丸中的类固醇生成。
DOI：
10.1016/0041-008x(91)90193-i
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发表时间：
1991
影响因子：
3.8
通讯作者：
Peterson,RE
中科院分区：
文献类型：
--
作者：
Moore,RW;Jefcoate,CR;Peterson,RE
在2，3，7，8-四氯二苯并-对-二恶英（TCDD）处理的大鼠中，睾酮合成减少，这是因为睾丸产生的双烯醇酮受到抑制。这种抑制只能由将胆固醇转化为胆固醇烯醇酮的线粒体酶（细胞色素P450 SCC）活性降低和/或促黄体生成素（LH）刺激胆固醇向该酶动员的多步过程受损引起。100 μ gTCDD/kg染毒7天后，睾丸细胞色素P450活性（以20α-羟基胆固醇为底物测定）下降至对照组的45%。如果这种减少是体内睾丸类固醇生成抑制的原因，那么睾丸中细胞色素P450的底物库将增加。然而，TCDD降低了容易获得的细胞色素P450 sccin分离的睾丸线粒体（反应性胆固醇池）的胆固醇的量，即使在体内LH类似物人绒毛膜促性腺激素（hCG）最大限度地刺激类固醇生成。底物池的这些减少不是由于反应性胆固醇的线粒体能力降低。我们的结论是，细胞色素P450 scc活性下降55%是不够严重，以抑制体内睾丸类固醇的生成。相反，TCDD必须通过抑制LH刺激的胆固醇向细胞色素P450 SCC的动员来发挥作用。这一结论得到两项意见的支持。首先，当用细胞色素P450 SCC抑制剂氨鲁米特治疗大鼠，阻断双烯醇酮的形成时，TCDD大大降低了hCG引起活性胆固醇在体内睾丸线粒体中积累的速率。第二，TCDD抑制睾酮的合成和动员胆固醇细胞色素P450 SCC在1天内。类固醇生成抑制似乎不是由于LH受体缺陷，因为TCDD抑制二丁酰cAMP和hCG刺激的类固醇分泌的离体灌注睾丸相当的程度。我们的结论是，TCDD抑制睾丸类固醇生成主要是通过抑制胆固醇的细胞色素P450 SCC的动员，如果不是唯一的，这种抑制发生在cAMP的形成。
Testosterone synthesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats is decreased because pregnenolone production by the testis is inhibited. This inhibition can only be caused by a reduction in the activity of the mitochondrial enzyme which converts cholesterol into pregnenolone (cytochrome P450scc), and/or by an impairment in the multistep process by which luteinizing hormone (LH) stimulates the mobilization of cholesterol to this enzyme. Seven days after rats were treated with 100 μg TCDD/kg, testicular cytochrome P450sccactivity (assayed with 20α-hydroxycholesterol as substrate) was decreased to 45% of control. If this decrease were responsible for the inhibition of testicular steroidogenesis in vivo, substrate pools for cytochrome P450sccin the testis would be increased. Yet TCDD decreased the amount of cholesterol that was readily available to cytochrome P450sccin isolated testis mitochondria (the reactive cholesterol pool), even when steroidogenesis was maximally stimulated in vivo with the LH analogue human chorionic gonadotropin (hCG). These decreases in substrate pools were not due to a reduction in mitochondrial capacity for reactive cholesterol. We conclude that the 55% decrease in cytochrome P450sccactivity is not severe enough to inhibit testicular steroidogenesis in vivo. Instead, TCDD must act by inhibiting the LH-stimulated mobilization of cholesterol to cytochrome P450scc. This conclusion is supported by two observations. First, when pregnenolone formation was blocked by treating rats with the cytochrome P450sccinhibitor aminoglutethimide, TCDD greatly reduced the rate at which hCG caused reactive cholesterol to accumulate in testis mitochondria in vivo. Second, TCDD inhibited both testosterone synthesis and the mobilization of cholesterol to cytochrome P450sccwithin 1 day. The steroidogenic inhibition does not appear to be due to an LH receptor defect, because TCDD inhibited dibutyryl cAMP- and hCG-stimulated steroid secretion by isolated perfused testes to comparable extents. We conclude that TCDD inhibits testicular steroidogenesis predominantly if not exclusively by inhibiting the mobilization of cholesterol to cytochrome P450scc, and that this inhibition occurs subsequent to cAMP formation.
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DOI：
10.1016/0005-2760(75)90167-8
发表时间：
1975
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
G. J. van der Vusse;M. L. Kalkman;M. P. Van Winsen;H. van der Molen
通讯作者：
H. van der Molen
促黄体素刺激的大鼠睾丸细胞质组分对正常大鼠睾丸线粒体产生孕烯醇酮的影响。
DOI：
10.1016/0304-4165(78)90068-5
发表时间：
1978
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
C. Bakker;M. P. van der Plank;H. van der Molen
通讯作者：
H. van der Molen
影响因子：
4.8
作者：
J. G. Ghazarian;C. Jefcoate;J. Knutson;W. Orme-Johnson;H. DeLuca
通讯作者：
J. G. Ghazarian;C. Jefcoate;J. Knutson;W. Orme-Johnson;H. DeLuca
影响因子：
3.8
作者：
BOOKSTAFF, RC;MOORE, RW;PETERSON, RE
通讯作者：
PETERSON, RE
2,3,7,8-四氯二苯并-对-二恶英治疗的雄性大鼠中垂体激素的血浆浓度。
DOI：
10.1002/jbt.2570040305
发表时间：
1989
期刊：
Journal of biochemical toxicology
影响因子：
--
作者：
Moore,RW;Parsons,JA;Bookstaff,RC;Peterson,RE
通讯作者：
Peterson,RE