Gasser Benedikt Andreas, Kurz Johann, Dick Bernhard, Mohaupt Markus Georg
Departement für Bewegung und Sport, Universität Basel, 4001 Basel, Switzerland.
Intersci Research Association, Karl Morre Gasse 10, 8430 Leibnitz, Austria.
Life (Basel). 2022 Jun 10;12(6):867. doi: 10.3390/life12060867.
Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha hydroxylase) and C17/20 lyase activity. However, to what extent steps are altered in affected children with autism versus healthy controls remains to be elucidated. Urine samples from 48 boys with autism (BMI 19.1 ± 0.6 kg/m, age 14.2 ± 0.5 years) and a matched cohort of 48 healthy boys (BMI 18.6 ± 0.3 kg/m, 14.3 ± 0.5 years) as well as 16 girls with autism (BMI 17.5 ± 0.7 kg/m, age 13.8 ± 1.0 years) and a matched cohort of 16 healthy girls (BMI 17.2 ± 0.8 kg/m, age 13.2 ± 0.8 years) were analyzed for steroid hormone metabolites by gas chromatography-mass spectrometry. The activity of 17-alpha Hydroxylase increased by almost 50%, whereas activity of 17/20 Lyase activity increased by around 150% in affected children with autism. Furthermore, the concentration of Cortisol was higher as compared to the average increase of the three metabolites TH-Corticosterone, 5α-TH-Corticosterone and TH-11β-DH-Corticosterone, indicating, in addition, a stimulation by the CRH-ACTH system despite a higher enzymatic activity. As it was shown that oxidative stress increases the 17/20-lyase activity via p38α, a link between higher steroid hormone levels and oxidative stress can be established. However, as glucocorticoid as well as androgen metabolites showed higher values in subjects affected with autism as compared to healthy controls, the data indicate, despite higher CYP17A1 activity, the presence of increased substrate availability in line with the Cholesterol theory of autism.
越来越多的证据表明，自闭症患者体内雄激素水平较高。有证据表明细胞色素P450 17A1（CYP17A1）具有易感性作用，它通过羟化酶活性（17-α羟化酶）和C17/20裂解酶活性催化两种不同类型的底物氧化。然而，与健康对照相比，自闭症患儿体内这些步骤的改变程度仍有待阐明。对48名自闭症男孩（体重指数19.1±0.6kg/m，年龄14.2±0.5岁）及其匹配的48名健康男孩队列（体重指数18.6±0.3kg/m，14.3±0.5岁），以及16名自闭症女孩（体重指数17.5±0.7kg/m，年龄13.8±1.0岁）及其匹配的16名健康女孩队列（体重指数17.2±0.8kg/m，年龄13.2±0.8岁）的尿液样本进行气相色谱-质谱分析，以检测类固醇激素代谢物。在自闭症患儿中，17-α羟化酶的活性增加了近50%，而17/20裂解酶的活性增加了约150%。此外，与三种代谢物四氢皮质酮、5α-四氢皮质酮和四氢-11β-脱氢皮质酮的平均增加量相比，皮质醇的浓度更高，这表明，尽管酶活性较高，但促肾上腺皮质激素释放激素-促肾上腺皮质激素系统仍有刺激作用。研究表明氧化应激通过p38α增加17/20-裂解酶的活性，因此可以建立较高的类固醇激素水平与氧化应激之间的联系。然而，与健康对照相比，自闭症患者的糖皮质激素以及雄激素代谢物的值更高，数据表明，尽管CYP17A1活性较高，但根据自闭症的胆固醇理论，底物可用性增加。
