Cytochrome P-450, in liver

Shu, Y., Cheng, Z. N., Liu, Z. Q. et al. (2001). Interindividual variations in levels and activities of cytochrome P-450 in liver microsomes ofChinese subjects. Acta Pharmacologica Sinica, 22(3),... 

Paine, A. J. and Hockin, L. J. (1980). Nutrient imbalance causes the loss of cytochrome P-450 in liver cell culture formulation of culture media which maintain cytoch rome P-450 at in vivo concentrations. Biochem. Pharmacol. 29 3215-3218. 

Masuda Y, Yasoshima M. 1988. Loss of 3-methylcholanthrene-inducible form of cytochrome P-450 in liver microsomes following administration of carbon disulfide in C57BL/6 Cr mice. Biochem Pharmacol 37 2363-2371. 

New spectral species associated with cytochrome P-450 in liver microsomes. Chem. Biol. Interact. 3, 260-261. 

Kamataki, T., M. Shimada, K. Maeda, and R. Kato (1985). Pituitary regulation of sex-specific forms of cytochrome P-450 in liver microsomes of rats. Biochem. Biophys. Res. Commun. 130, 1247-1253. 

Ohmori S, Kuriya S, Uesugi T, Horie T, Sagami F, Mikami T, Kawaguchi A, Rikihisa T, Kanakubo Y. Decrease in the specific forms of cytochrome P-450 in liver microsomes of a mutant strain of rat with hyperbilirubinuria. Res Commun Chem Pathol Pharmacol 1991 72 243-253. 

Yoshida Y, Kumaoka H (1975) Studies on the substrate-induced spectral change of cytochrome P-450 in liver microsomes. J Biochem 78 55-68... 

In the absence of added substrate, NADPH continuously reduces cytochrome P-450 and the reduced form of cytochrome P-450 is continuously reoxidized. Whether this cyclic process of oxidation and reduction of cytochrome P-450 rq>re-sents metabolism of normal substrates present in liver microsomes ronains unknown, but it may be important that cytochrome P-450 enzymes in liver microsomes catalyse the hydroxylation of cholesterol and the co-oxidation df fatty adds. In any event, the rate of cytochrome P-450 oxidation by NADPH is about an order of magnitude greater than the rate of cytochrome P-450 reduction. Indeed, it seems likely that in the presence of an NADPH-generating system and air under steady-state conditions as much as 90% of the cytochrome P-450 in liver microsomes may be in the oxidized form. 

These findings suggest that liver microsomes contain at least two different cytochrome P-450 s each of which is present as two interconvertible forms. It is still possible that microsomes contain other fimctionally different cytochromes which have thus far not been identified. The concept of a number of fimctionally different cytochrome P-450 in liver microsomes could account for the marked variations in the pattern of drug metabolism found in various animal species or after various treatments. At the present time, however, it seems likely that any form of cytochrome P-450 may catalyse a number of different reactions and that any of the reactions may be catalysed by a number of different forms of cytochrome P-450. For this reason the various enzymes should not be referred to simply as demethyl-ases, hydroxylases, deaminases, etc., without refo-ring to the substrate. 

Komori M, Nishio K, Kitada M, et al. 1990. Fetus-specific expression of a form of cytochrome P-450 in human liver. Biochemistry 29 4430-4433. 

Van Veld, P.A., D.J. Westbrook, B.R. Woodin, R.C. Hale, C.L. Smith, R.J. Huggett, and JJ. Stegeman. 1990. Induced cytochrome P-450 in intestine and liver of spot (Leiostomus xanthurus) from a polycyclic aromatic hydrocarbon contaminated environment. Aquat. Toxicol. 17 119-132. 

Cytochrome P-450 in Fish Liver Microsomes and Carcinogen Activation... 

Schuetz EG, Schuetz JD, Strom SC, Thompson MT, Fisher RA, Molowa DT, Li D, Guzelian PS (1993) Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes. Hepatology 18 1254— 1262. 

Miki H, Takeuchi H, Yamada A, Nishioka M, Matsuzawa Y, et al. 1986. Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27 in livers of patients with cerebrotendinous xanthomatosis. Clin Chim Acta 160 255-263. 

De Groot H, Noll T. 1989. Halomethane hepatotoxicity Induction of lipid peroxidation and inactivation of cytochrome P-450 in rat liver mierosomes under low oxygen partial pressures. Toxieol Appl Pharmaeol 97 530-537. 

Induced in the supernatant of the Sprague-Dawley rats (46%). Phenobarbital is considered to be an inducer of some, but not all, cytochrome P-450-dependent enzyme activity (21, 23). In line with the present results, Jori and Pescador (24) found that the level of cytochrome P-450 in the microsomal pellet from the livers of Long-Evans rats was induced by 47 percent by phenobarbital. Our level of induction was smaller but in the same direction. These data strongly support the presence of more than one nitrosamine demethylase in the liver. 

The converse is true of drugs requiring metabolic activation for toxicity. For example, paracetamol is less hepatotoxic to newborn than to adult mice, as less is metabolically activated in the neonate. This is due to the lower levels of cytochromes P-450 in neonatal liver (Fig. 5.30). Also involved in this is the hepatic level of glutathione, which is required for detoxication. Although levels of this tripeptide are reduced at birth, development is sufficiently in advance of cytochrome P-450 levels to ensure adequate detoxication (Fig. 5.30). The same effect has been observed with the hepatotoxin bromobenzene. (For further details of paracetamol and bromobenzene see chap. 7.) Similarly, carbon tetrachloride is not hepatotoxic in newborn rats as metabolic activation is required for this toxic effect, and the metabolic capability is low in the neonatal rat. 

Thus, induction can change the proportions of isoenzymes in a particular tissue and may increase the activity of a normally insignificant form by many times. Although phenobarbital induction increases the overall concentration of cytochromes P-450 in the liver by about threefold, specific isoenzymes may be increased up to 70-fold. Treatment with 3-methylcholanthrene can increase a specific form of the enzyme by a similar order. 

Halpert, J.R., Balfour. C., Miller, N.E. Kaminsky, L.S. (1986) Dichloromethyl compounds as mechanism-based inactivators of rat liver cytochromes P-450 in vitro. Mol. Pharmacol., 30, 19-24... 

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