CYTOCHROME P450(11-BETA) - STRUCTURE-FUNCTION RELATIONSHIP OF THE ENZYME AND ITS INVOLVEMENT IN BLOOD-PRESSURE REGULATION

Cytochrome P450(11 beta) is deeply involved in the final steps of bios ynthesis of mineralocorticoids. This paper deals with following issues about this enzyme. (1) The structure and function of the enzymes of v arious animal species are discussed. By making alignment of amino acid sequences of the enzymes, we identified peptide domains essential for the enzyme actions such as a putative steroid binding domain and a he me binding region. Estimates of molecular similarity among the P450(11 beta) family enzymes suggested that the enzymes having both 11 beta-h ydroxylation activity and aldosterone (ALDO) synthetic activity of cer tain animals such as frog, cattle and pig are more similar to the ALDO synthases of the other animals, such as rat, mouse and human, than th e 11 beta-hydroxylases of these animals. (2) The molecular nature of t he P450(11 beta) family enzymes of genetically hypertensive rats as we ll as adrenal regeneration hypertension (ARH) rats is examined. (i) Mu tation was found in the P450(11p) gene of Dahl's salt-resistant normot ensive rat. Steroidogenic activity expressed by the mutated gene accou nted well for abnormal plasma levels of steroid hormones in this rat. (ii) 11 beta-, 18- and 19-Hydroxylation activities of adrenal mitochon dria prepared from spontaneously hypertensive rat (SHR), Wistar-kyoto rat (WKY), and stroke-prone (SP)-SHR were not significantly different from each other. Levels of mRNA of ALDO synthase in adrenal glands of 50-week-old SHR was significantly lower than those of 10-week-old SHR, WKY and SHR-SP. (iii) No significant difference in 19-hydroxylation a ctivity was found between adrenal mitochondria prepared from ARH rat a nd those from control rat. The level of message of ALDO synthase was l ower in adrenal glands of ARH rat.