Enzymes cytochrome, inactivation

Reichhart, D., Simon, A., Durst, F., Mathews, J.M., and Ortiz de Montellano, P.R., Autocatalytic inactivation of plant cytochrome P-450 enzymes selective inactivation of cinnamic acid 4-hydroxylase from Helianthus tuberosus by 1-aminobenzotriazole, Arch. Biochem. Biophys., 216, 522-529, 1982. 

D. Ketoconazole inhibits cytochrome P-450 enzymes that inactivate cyclosporine. 

The correct answer = D. Ketoconazole is effective against Candida, but it does not react with cyclosporine nor is it cardiotoxic. Ketoconazole inhibits the hepatic cytochrome P-450 enzymes that inactivate cyclosporine. Thus in this instance the patient would be in danger of increased cyclosporine toxicity. Though ketoconazole does cause gynecomastia and decreased libido, this would not be of primary concern. 

The cytochrome P-450-catalyzed oxidation of N.N-bis-carbethoxy-2,3-diazabicyclo[2,2,0]hex-5-ene (, R = C02Et), a relatively stable derivative, results in time-dependent inactivation of the enzyme.The inactivation is paralleled by the accumulation of a heme adduct Identified as N-(2-cyclobutenyl)protoporphyrin IX, a finding that points to a catalytically unmasked cyclobutadlenoid species as the heme-alkylating agent. 

Faber stages 52/53, 57/58, and 61/62 (Kistler and Weber, 1974). Since tail muscle regresses during metamorphosis in response to thyroxine, the larvae were reared in thiourea in order to inactivate the thyroid glands. Such treatment presumably has no effect on the level of enzymic activity. As was also noted in the case of liver mitochondria, during the same period of development, the specific activities of the membrane-bound enzymes, cytochrome a - - as and succinate dehydrogenase, remain... 

Kent UM, Mills DE, Rajnarayanan RV, et al. Effect of 17-alpha-ethynylestradiol on activities of cytochrome P450 2B (P450 2B) enzymes characterization of inactivation of P450s 2B1 and 2B6 and identihcation of metabolites. J Pharmacol Exp Ther 2002 300(2) 549-558. 

Kassahun K, Skordos K, McIntosh I, et al. Zafirlukast metabolism by cytochrome P450 3A4 produces an electrophilic alpha,beta-unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme. Chem Res Toxicol 2005 18(9) 1427-1437. 

Obach, R.S., Walsky, R.L. and Venkatakrishnan, K. (2007) Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions. Drug Metabolism and Disposition, 35 (2), 246—255. 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

With the exception of two dehydrogenases, all of the steroidogenic enzymes belong to the cytochrome P-450 (abbreviated as CYP) family of enzymes. The CYP enzymes are often involved with redox or hydroxylation reactions, and are also found in the liver where they are key players in biotransformation reactions (see Section 6.4). Different members of the CYP family are therefore involved with both synthesis in adrenal and gonads and hepatic inactivation of steroid hormones. 

H. Cai, F. P. Guengerich, Acylation of Protein Lysines by Trichloroethylene Oxide , Chem. Res. Toxicol. 2000,13, 327 - 335 H. Cai, F. P. Guengerich, Reaction of Trichloroethylene and Trichloroethylene Oxide with Cytochrome P450 Enzymes Inactivation and Sites of Modification , Chem. Res. Toxicol. 2001, 14, 451 - 458. 

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