Cytochrome drugs

ChenH, Howald WN, and Juchau MR (2000) Biosynthesis of all-fraws-retinoic acid from all-fraws-retinol catalysis ofall-trfl s-retinol oxidation by human P-450 cytochromes. Drug Metabolism and Disposal 28, 315-22. 

In general, the detection of adverse drug reactions early in the drug discovery process is becoming commonplace. So-called liability panels of receptors, hERG channel activity, and cytochrome enzymes are utilized to identify... 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

Cytochrome P450 2D6, also termed debrisoquine-sparteine hydroxylase, is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of several tricyclic antidepressants, antipsychotics, beta-blockers, opioids, and many other drugs. 

Cytochrome P450 2C9 Low activity in about 10% (heterozygotes) and very low activity in about 0.8% (homozygotes) of Caucasian populations. Prolonged action of several CYP2C9 inactivated drugs like phenytoin, tolbutamide, ibuprofen, or S-warfarin. 

Cytochrome P450 2C19 Deficient activity in about 3% of Caucasian populations and in about 20% of Asian populations. Prolonged action of several CYP2C19 inactivated drugs like omeprazole or diazepam in the poor metabolizers. 

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

Abelo A, Andersson TB, Antonsson M et al (2000) Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 28 966-972... 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Shi J, Hui L, Xu Y, et al Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 19 459 60, 2002 Shinderman M, Maxwell S, Brawand-Arney M, etal Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses. Drug Alcohol Dependence 69 205-211, 2003... 

Sagir A, Schmitt M, Dilger K, Haussinger D (2003) Inhibition of cytochrome P450 3A relevant drug interactions in gastroenterology. Digestion 68 41 8... 

Zhong W, Uss AS, Ferrari E, Lau JY, Hong Z (2000) De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase. J Virol 74 2017-2022 Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M, McLeod HL (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharma-cokinet 44 279-304... 

Evidence suggests that endosulfan can induce microsomal enzyme activity. Increased liver microsomal cytochrome P-450 activity was observed in male and female rats after single and multiple administrations of endosulfan (Siddiqui et al. 1987a Tyagi et al. 1984). Increased enzyme activity was observed in hepatic and extrahepatic tissues. Based on the increase in aminopyrine-A-demethylase and aniline hydroxylase activity, endosulfan has been shown to be a nonspecific inducer of drug metabolism (Agarwal et al. 1978). 

Since endosulfan is a cytochrome P450-dependent monooxygenase inducer, the quantification of specific enzyme activities (e.g., aminopyrine-A -demethylase, aniline hydroxylase) may indicate that exposure to endosulfan has occurred (Agarwal et al. 1978). Because numerous chemicals and drugs found at hazardous waste sites and elsewhere also induce hepatic enzymes, these measurements are nonspecific and are not necessarily an indicator solely of endosulfan exposure. However, these enzyme levels can be useful indicators of exposure, together with the detection of endosulfan isomers or the sulfate metabolite in the tissues or excreta. 

Ekins S, De Groot MJ, Jones JP. Pharmacophore and three-dimensional quantitative structure activity relationship methods for modeling cytochrome P450 active sites. Drug Metab Dispos 2001 29 936-44. 

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