Cytochrome P450 isozymes

Cytochrome P450 (CYP) Cytochrome P450 isozymes Cytochrome P450 mono-oxygenases Mixed function oxidases... 

Other drag molecules can behave as inhibitors of specific cytochrome P450s. Inhibition of cytochrome P450 isozymes can lead to a slowing down of the metab-... 

Figure 1.10 Relative contributions of different cytochrome P450 isozymes to drug metabolism in humans.

The virtual compounds can be screened against structural models of the metabolizing enzymes, including the known SNP variants. These procedures are becoming widely adopted for the cytochrome P450 isozymes involved in oxidative drug metabolism. 

Arylthioethylsydnone 73 (TTMS) is known to act as a mechanism-based inhibitor of some cytochrome P450 isozymes and as an inducer of cytochrome P450 3A <1996MI676, 1996MI872, 1998MI739>. 

Lapadula DM, Habig C, Gupta RP, et al. 1991. Induction of cytochrome P450 isozymes by simultaneous inhalation exposure of hens to n-hexanc and methyl iso-butyl ketone (MiBK). Biochem Pharmacol 41(6-7) 877-883. 

Nakajima T, Elovaara E, Park SS, et al. 1991. Immunochemical detection of cytochrome P450 isozymes induced in rat liver by -hexanc, 2-hexanone and acetyl acetone. Arch Toxicol 65 542-547. 

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

Fonne-Pfister R, Bargetzi MJ, Meyer UA. 1987. MPTP, the neurotoxin inducing Parkinson s disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufl, P450dbl) catalyzing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun 148 1144-1150. 

Masubuchi Y, Hosokawa S, Horie T, Suzuki T, Ohmori S, et al. 1994. Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes. The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopro-pylase. Drug Metab Dispos 22 909-915. 

Yu AM, Granvil CP, Raining RL, Krausz KW, Corchero J, et al. 2003. The relative contribution of monoamine oxidase and cytochrome p450 isozymes to the metabolic deamination of the trace amine tryptamine. J Pharmacol Exp Ther 304 539-546. 

Dalet-Beluche 1, Boulenc X, Eabre G, Maurel P, Bonfils C (1992) Purification of two cytochrome P450 isozymes related to CYP2A and CYP3A gene families from monkey (baboon, Papio papio) liver microsomes. Cross reactivity with human forms. Eur J Biochem 204 641-648 Damaj Ml, Siu EC, Sellers EM, Tyndale RE, Martin BR (2007) Inhibition of nicotine metabolism by methoxysalen Pharmacokinetic and pharmacological studies in mice. J Pharmacol Exp Ther 320 250-257... 

Table 3.3. Main types of drug metabolized by cytochrome P450 isozymes...

Nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Nateglinide is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Lewis, D. F. and Lake, B. G. (1998) Molecular modelling and quantitative structure-activity relationship studies on the interaction of omeprazole with cytochrome P450 isozymes. Toxicology 125, 31-44. 

A) Abnormal heart rhythms alcohol induces cytochrome P450 isozymes that convert ibuprofen to a cardiotoxic free radical metabolite... 

Perkins E. and D. Schlenk (1998). Immunochemical characterization on hepatic cytochrome P450 isozymes in the channel catfish Assessment of sexual, development and treatment-related effects. Comparative Biochemistry and Physiology C 121 305-310. 

Yu, C., Shin, Y.G., Kosmeder, J.W., Pezzuto, J.M., and van Breemen, R.B., Liquid chromatog-raphy/tandem mass spectrometric determination of inhibition of human cytochrome P450 isozymes by resveratrol and resveratrol-3-sulfate. Rapid Commun. Mass Spectrom., 17, 307, 2003. 

Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996 50(3) 209-215. 

The amide linkage of amide local anesthetics is hydrolyzed by liver microsomal cytochrome P450 isozymes. There is considerable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest)... 

Nakajima, T.. Wang, R.-S., Elovaara, E., Park, S.S., Gelboin, H.V., Hietanen. E. Vainio, H. (1991) Monoclonal antibody-directed characterization of cytochrome P450 isozymes responsible for toluene metabolism in rat liver. Biochem. Pharmacol., 41, 395-404... 

Wang, R.S., Nakajima, T., Tsuruta. H. Honma, T. (1996) Effect of exposure to four organic solvents on hepatic cytochrome P450 isozymes in rat. Chem.-biol. Interact., 99, 239-252 Whittaker, S.G, Zimmermann, F.K.. Dicus, B., Piegorsch, W.W, Resnick, M.A. Fogel, S. 

Raunio, H., Liira, J., Elovaara, E., Riihimaki, V. Pelkonen, O. (1990) Cytochrome P450 isozyme induction by methyl ethyl ketone and wz-xylene in rat liver. Toxicol, appl. Pharmacol., 103, 175-179... 

Phenobarbital is utilized as a daytime sedative and anticonvulsant. It also induces several cytochrome P450 isozymes. Compared to other barbiturates, phenobarbital has a low oil/water partition coefficient, which results in slow distribution into the brain. It is available for oral, intravenous, or intramuscular administration. Doses for epileptic patients range from 60 to 200 mg per day. After a single oral dose of 30 mg, peak serum concentrations averaged 0.7 mg/L (n = 3). Repeated doses over a period of 7 days resulted in an average peak concentration of 8.1 mg/L.6 Chronic administration of 200 mg per day as anticonvulsant medication resulted in an average blood concentration of 29 mg/L (range = 16 to 48 mg/L).8... 

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