Bradlow H L, Gillette P N, Gallagher T F, Kappas A
J Exp Med. 1973 Oct 1;138(4):754-63. doi: 10.1084/jem.138.4.754.
Patients with the genetic liver disease, acute intermittent porphyria (AIP), have a defect in the reductive transformation of steroid hormones that is manifest by the disproportionate generation of 5beta-steroid metabolites from precursor hormones. 5beta-steroid metabolites were earlier shown to be potent inducers experimentally of delta-aminolevulinate synthetase (ALAS), the mitochondrial enzyme that is rate-limiting in porphyrin synthesis, and that is found at high levels of activity in the livers of AIP patients. In this report, the basis for the defective steroid metabolism in AIP has been shown, through studies with the (14)C-labeled adrenal hormone 11beta-hydroxy-Delta(4)-androstenedione, to reside in a substantial deficiency of hepatic steroid Delta(4)-5alpha-reductase activity. This enzymic deficiency was found in all seven AIP patients studied, and ranged from 34% to as much as 70% below the mean enzyme activity characterizing normal subjects. The functional consequence of the low levels of 5alpha-reductase activity in AIP is to divert the reductive transformation of certain natural hormones from the 5alpha- to the 5beta-pathway; the latter is the metabolic route through which endogenous steroids having the potential for inducing hepatic ALAS are generated. It is not presently known whether the 5alpha-reductase deficiency in AIP is acquired in some fashion or whether it has partial genetic determinants. It seems probable, however, that this enzymatic abnormality, coupled with the dramatic increase in hormone synthesis that occurs at puberty, may be of major importance in determining clinical expression of the latent gene defect for AIP in many individuals. The 5alpha-reductases for steroid hormones are known to be localized in the endoplasmic reticulum of hepatic cells and the present findings in AIP thus represent the first demonstration that an enzymic component of these membranous structures is functionally abnormal in this hereditary liver disease.
患有遗传性肝病急性间歇性卟啉病（AIP）的患者，其甾体激素的还原转化存在缺陷，表现为前体激素不成比例地生成5β-甾体代谢物。5β-甾体代谢物早些时候在实验中被证明是δ-氨基-γ-酮戊酸合成酶（ALAS）的有效诱导剂，ALAS是卟啉合成中的限速线粒体酶，在AIP患者肝脏中活性水平很高。在本报告中，通过对（14）C标记的肾上腺激素11β-羟基-δ（4）-雄烯二酮的研究表明，AIP中甾体代谢缺陷的基础在于肝脏甾体δ（4）-5α-还原酶活性的显著缺乏。在所研究的所有7名AIP患者中均发现了这种酶缺乏，其活性比正常受试者的平均酶活性低34%至多达70%。AIP中5α-还原酶活性水平低的功能后果是将某些天然激素的还原转化从5α途径转移到5β途径；后者是生成具有诱导肝脏ALAS潜力的内源性甾体的代谢途径。目前尚不清楚AIP中的5α-还原酶缺乏是以某种方式获得的，还是具有部分遗传决定因素。然而，这种酶异常，再加上青春期激素合成的显著增加，在许多个体中可能对决定AIP潜在基因缺陷的临床表达起重要作用。已知甾体激素的5α-还原酶定位于肝细胞的内质网，因此AIP中的目前发现首次证明了这些膜结构的一种酶成分在这种遗传性肝病中功能异常。
