Steroid 27-hydroxylase

Figure 11-6. Cytochrome P450 hydroxylase cycle in microsomes. The system shown is typical of steroid hydroxylases of the adrenal cortex. Liver microsomal cytochrome P450 hydroxylase does not require the iron-sulfur protein FejSj. Carbon monoxide (CO) inhibits the indicated step.

Berg A, JA Gustafsson, M Ingelman-Sundberg, K Carlstrdm (1976) Characterization of a cytochrome P-450-dependent steroid hydroxylase present in Bacillus megaterium. J Biol Chem 251 2831-2838. 

Guo J., Dudley C., Su T., Spink D., et al. (1999). Cytochrome P450 and steroid hydroxylase activity in mouse olfactory and vomeronasal mucosa. Biochem Biophys Res Comm 266, 262-267. 

T. Kimura, J. J. Ting, and J. J. Huang, Studies on adrenal steroid hydroxylases. Anomalous fluorescence of a tyrosyl residue in adrenal iron-sulfur protein (adrenodoxin), J. Biol. Chem. 247, 4476-4479 (1972). 

SALICYLATE 1-MONOOXYGENASE SARCOSINE OXIDASE STEROID HYDROXYLASES SULFITE OXIDASE SULEUR DIOXYGENASE THYMIDINE 2 -HYDROXYLASE TOLUENE DIOXYGENASE XANTHINE OXIDASE... 

Figure 5. Role of megaredoxin in steroid hydroxylase system of B. megaterium...

NADPH NADPH-adrenodoxin reductase (fp), adrenodoxin (Fe-S) P-450 Adrenal mitochondrial steroid hydroxylase 36-39)... 

Various studies have shown that ketoconazole interferes with 17- and 20-hydroxylases and inhibits mitochondrial 11-a-hydroxylase and cytochrome P450-dependent steroid hydroxylase enzymes (SED-12, 677 SEDA-12, 228 SEDA-14, 234) (584). 

Domanski TL, Liu J, Harlow GR, Halpert JR (1998) Analysis of four residues within substrate recognition site 4 of human cytochrome P450 3A4 role in steroid hydroxylase activity and a-napthoflavone stimulation. Arch Biochem Biophys 350, 223-232. 

ACTH has several other effects on adrenocortical cell metabolism. It increases the synthesis of adrenocortical cell phospholipids this may also have a long-term supportive role for increased steroidogenic capacity. It increases the rate of glycolysis in the adrenocortical cell this may have a supportive role in the supply of pyruvate for the mitochondrial steroid hydroxylases [32],... 

Congenital Adrenal Hyperplasia P450c21 Steroid Hydroxylase Deficiency... 

Why are ACTH levels elevated in patients with P450c21, P450cl7, and P45011 3 steroid hydroxylase deficiency ... 

The nature of the enzyme responsible for the hydroxylation reaction has long been unidentified it has been, however, recognized that the steroid 11 p-hydroxylase consists of at least three components which can be separated by ordinary purification procedures. This observation leads us to assume that the steroid hydroxylase has the nature of a multiple enzyme complex. 

Redox components of adrenal steroid hydroxylase. In biological and chemical aspects of oxygenases, p. 179. K. Bloch and O. Hayaishi, ed. Tokyo Maruzen 1966. 

Figure 6.2. Scematic presentation of the Cytochrome P 450cam active site (a) and the Breslow model of steroid hydroxylase (Groves, 1997). Reproduced with permission.

The cytochome P-450 systems of the steroid producing tissues have many characteristics in common with those of the liver and other xenobiotic-metabolizing tissues. They require NADPH and molecular oxygen, and contain a flavoprotein, NADPH cytochrome P-450 reductase. Unlike the systems in the liver, however, the steroid hydroxylases are associated with both the endoplasmic reticulum and the mitochondria and are quite specific for the different reactions that they catalyze. Thus, adrenal microsomes... 

As with the mixed-function oxidases involved in xenobiotic metabolism, the substrate specificity of the steroid hydroxylases is dictated, in part, by the existence of multiple forms of both microsomal and mitochondrial cytochrome P-450s and further opportunities for specificity are provided by the distinct localization of the various enzymes in either the mitochondria or the endoplasmic reticulum. 

While the hydroxylases of the adrenals and other steroid producing tissues show some (variable) catalytic activity towards xenobiotics (e.g., benzo[a]pyrene) (17) this is probably fortuitous in nature and it seems that, in general, the enzymes are quite specific for their respective steroid substrates. Furthermore, the steroid hydroxylases of the endocrine system are not susceptible to the inductive effects of xenobiotics as are the cytochrome P-450-mediated oxidases of the liver and other tissues (17,18) indeed, this is not unexpected, since if they responded to the external environment in this way their critical homeostatic role would rapidly be compromized. 

Welch RM, Levin W, Conney AH. 1967. Insecticide inhibition and stimulation of steroid hydroxylases in rat liver. J. Pharmacol. Exp. Ther. 155 167-73... 

Another classical example of a tissue-specific toxicity is the effect of o,//-DDD on the 11 /3-hydroxylase, a key steroidogenic enzyme present only in the adrenal tissue. In this particular case, the enzymes effecting steroid production are the specific targets for adrenal toxicants. Steroid hydroxylases contain hemoproteins, constituents that make them vulnerable to toxicants and oxidative stress54. The adrenotoxic effects of DDT and its derivatives, and the sensitivity of the 11 /3-hydroxylase to DDT have been detected in numerous species, including humans. A derivative of DDT, under the name mitotane, was in fact used clinically in chemotherapy treatments for tumors in the adrenal cortex93 as it specifically destroys adrenal cells. The use of mitotane is similar... 

Occasionally, the cytochrome P-450 system converts some chemieals to reactive species with carcinogenic potential (e.g., polycyclic hydrocarbons). The hepatic microsomal cytochrome P-450 system is inducible by many of its substrates. The cytoehrome P-450 of adrenal cortical mitochondria is involved in steroid hydroxylase reactions, and this system contains iron-sulfur (Fc2S2) proteins. 

P450 17 Family (Steroid Subfamily (Steroid hydroxylases) CYP17... 

Wang, H. P., Pfeiffer, D. R., Kumura, T., and Teheu, T. T., Phospholipids of adrenal cortex mitochondria and the steroid hydroxylase The lipid environment of cytochrome P-450. Biochem. Biophys. Res. Commun. 57, 93-99 (1974). 

Sewer, M. B., and Waterman, M. R. (2003). ACTH modulation of transcription factors responsible for steroid hydroxylase gene expression in the adrenal cortex. Microsc Res Tech 61, 300-307. 

Inhibition of human aromatase by imidazole drugs has been extensively studied in vitro and in vivo [56, 115-120]. Ketoconazole has been most widely studied due to its widespread clinical use as an orally active broad-spectrum antimycotic and reports of associated gynaecomastia [109]. In vitro, it inhibits the aromatisation of both androstenedione [56] and testosterone [118], but is slightly less effective than AG (for example, K, values with androstenedione as substrate are 6,000 nM for ketoconazole and 4,400 nM for AG [56]). In contrast to AG, ketoconazole has been reported to be a non-competitive inhibitor of aromatase [116], although inhibition of other steroid hydroxylases is apparently competitive in nature [114] some other azoles such as miconazole have been reported to be competitive inhibitors [56]. 

Beilke, D., R. Weiss, F. Lohr, P. Pristovsek, F. Ffannemann, R. Bernhardt et al. (2002). A new electron transport mechanism in mitochondrial steroid hydroxylase systems based on structural changes upon the reduction of adrenodoxin. Biochemistry 41, 7969-7978. 

Vickery, L.E. (1997). Molecular recognition and electron transfer in mitochondrial steroid hydroxylase systems. Steroids 62, 124-127. 

Evidence for the cluster model of mitochondrial steroid hydroxylase system derived from dissociation constants of the complex between adrenodoxin reductase and adrenodoxin. Biochem. Biophys. Res. Commun. 276, 210-215. 

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