Cytochrome P450 system mitochondrial

Mitochondrial cytochrome P450 systems are found in steroidogenic tissues such as adrenal cortex, testis, ovary, and placenta and are concerned with the biosyn-... 

The cytochrome P450 system, found in microsomal and inner mitochondrial membranes (Figure IOC), consists of two enzymes NADPH-cytochrome P450 reductase and cytochrome 450 In each reaction two electrons are transferred one at a time from NADPH to a cytochrome P450 protein by NADPH cytochrome P450 reductase. The latter enzyme is a flavoprotein that contains both FAD and FMN in a ratio of 1 1 per mole of enzyme. 

In addition to these major processes, many other chemical events also occur. Mitochondria concentrate Ca2+ ions and control the entrance and exit of Na+, K+, dicarboxylates, amino acids, ADP, P and ATP, and many other substances.16 Thus, they exert regulatory functions both on catabolic and biosynthetic sequences. The glycine decarboxylase system (Fig. 15-20) is found in the mitochondrial matrix and is especially active in plant mitochondria (Fig. 23-37). Several cytochrome P450-dependent hydroxylation reactions, important to the biosynthesis and catabolism of steroid hormones and... 

The pattern of inhibition of 17a-hydroxylase exhibited by metyrapone lends further support to the hypothesis that cytochrome P450 is involved in the enzyme system319 whilst the effect of administration of spironolactone on the cytochrome P450 content and 17a-hydroxylase activity in adrenal tissue has shown that decreases in both of these factors occur only in animals that produce predominantly cortisol rather than corticosterone.320 18-Hydroxylation of deoxycorticosterone has been demonstrated in rat and bovine mitochondrial preparations and in reconstituted systems obtained from these fractions.321 In all cases, 18-hydroxylation was accompanied by 11/8-hydroxylation, and the study indicated that very similar types of cytochrome P450 were involved in both hydroxylation systems. 

The crystal structure of NADPH-cytochrome P450 reductase (CPR), the common electron-transfer protein of Class 11 eukaryotic P450 systems, was reported in 1997. This was followed by the structures of adrenodoxin reductase (AdR) and adrenodoxin (Adx), the two electron-transfer proteins of the Class 1 mitochondrial P450 system. The crystal structure of a cross-linked AdR-Adx complex has also been reported. " Putidaredoxin reductase (PdR) and putidaredoxin (Pd) of the P450cam system have also been structurally characterized. ... 

Ethyl benzene is an inducer of the cytochrome P450 and cytochrome c reductase enzyme systems. Ethyl benzene acts as a mitochondrial-uncoupling agent. It is believed that ethyl benzene metabolites are capable of interfering with dopamine catabolism in the brain. The tuberoinfundibular dopaminergic system may be a target for these metabolites. 

Protein-mediated electron transfer is a device used in a diverse array of biological transformadons. Well-known electron transfer processes include the mitochondrial electron transport system, photosynthesis (Chapter 13), and nitrogen flxadon (Chapter 15). Less well known biochemical reactions in which electron transfer plays a crucial role include nitric oxide synthesis and the cytochrome P450 electron transport systems. Each of these mechanisms is briefly oudined. 

Hepatic microsomes are among the most popular and widely employed systems in current use. These preparations retain activity of enzymes that reside in the smooth endoplasmic reticulum, such as cytochrome P450s, flavin monooxygenases, and glucuronosyltransferases. However, isolated hepatocytes and cell models in general retain a broader spectrum of enzymatic activities, including cytosolic and mitochondrial enzymes. 

The existence of mitochondrial cytochrome P450 in adrenal cortex was reported originally by Harding et al (1964) and confirmed by subsequent studies. Adrenal cortical mitochondria catalyze a number of NADPH- and molecular-oxygen-dependent hydroxylation reactions that contribute to the biosynthesis of corticosteroids. The enzyme system for 11 jS-hydroxyla-tion has been isolated, and a successful reconstitution of its activity has been achieved by the interaction of three proteins, namely an NADPH-dependent flavoprotein (adrenodoxin reductase), an iron-sulfur protein (adrenodoxin), and the heme protein (cytochrome P450) that serves as the terminal oxidase for the electron transport system from NADPH to oxygen (Wang and... 

---