Metabolism by Cytochrome

The table in (B) provides an overview of different CYP isozymes along with their substrates, inhibitors, and inducers. Obviously, Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

Rifampicin, carba-mazepine, dexa-methasone, pheny-toin, St.John s wort 

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As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

In the subsequent years, the mechanism of CCU hepatotoxicity has been more fully characterized, although the picture is still not complete. CCU is metabolized by cytochrome P450 in the endoplasmic... 

The present view of the mechanism of acute CCU hepatotoxicity is that it is metabolized by cytochrome P450 to CCI3, a large proportion of which reacts with oxygen to form CCI3OO. Neither radical can leave... 

Nateglinide (N) Starlix 60, 120 120 with meals 120 with meals NA 120 mg three times a day Up to 4 hours Metabolized by cytochrome P450 (CYP450) 2C9 and 3A4to weakly active metabolites renally eliminated... 

Ropinirole is initiated at 0.25 mg three times daily and increased by 0.25 mg three times daily on a weekly basis to a maximum of 24 mg/day. It is metabolized by cytochrome P450 1A2 fluoroquinolones and smoking may alter ropinirole clearance. 

No information is available on the adverse health effects of hexachloroethane in humans. Animal studies revealed that hexachloroethane primarily causes liver and kidney toxicity. Effects on the nervous system and lungs have also been reported. The mechanism by which these effects are mediated is not well characterized. Reductive metabolism by cytochrome P-450 and production of a free radical intermediate have been suggested as factors in hexachloroethane-induced hepatotoxicity (Nastainczyk et al. 1982a Thompson et al. 1984 Town and Leibman 1984). Accordingly, one possible approach may be to reduce free radical injury. To that end, oral administration of N-acetylcysteine can be used as a means of reducing free radical injury. Also, oral administration of vitamin E and vitamin C may be of value since they are free radical scavengers. 

Koop DR. Oxidative and reductive metabolism by cytochrome P450 2E1. Faseb J 1992 6(2) 724-730. 

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. 

Atkins, W.M. and Sligar, S.G. (1988) Deuterium isotope effects in norcamphor metabolism by cytochrome P-450cam kinetic evidence for the two-electron reduction of a high-valent iron-oxo intermediate. Biochemistry, 27 (5), 1610-1616. 

Watkins PB (1992) Drug Metabolism by Cytochromes P450 in the Liver and Small Bowel. Gastroenterol Clin North Am 21 pp 511-526. 

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

The precise mechanism of 1,4-dichlorobenzene oxidation to 2,5-dichlorophenol has not thoroughly been investigated. 1,4-Dichlorobenzene is known to be metabolized by cytochrome P-450 (Azouz et al. 1955 Hawkins et al. 1980) in order to be presented to phase II metabolic pathways to increase its water solubility for excretion. A proposed metabolic pathway involving cytochrome P-450 with intermediate formations of metabolites has been outlined for 1,4-dichlorobenzene (Den Besten et al. 1992). No... 

The nutritional value of the diet influences the ability of herbivores to detoxify plant secondary metabolites (Schwass and Finley, 1985). For instance, voles in winter have to consume the bark of birch Betula sp.). This causes stress and leads to poor growth and high mortality among young animals. Birch bark contains phenolics and terpenoids. Both are metabolized by cytochrome P450 monooxidases in phase I and conjugated with glucuronic acid in phase II. 

This agrees very much with the model proposed by Peterson et al. (8) for the 5-exo hydroxylation of d and 1 camphor in mammalian cytochrome P-450/ and is also consistent with the relationship they noted from steroid metabolism by cytochrome P-450/ between the position hydroxylated and its relation to a polar funtional group. 

Nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). 

D6 - Tolterodine is not expected to influence the pharmacokinetics of drugs that are metabolized by cytochrome P450 2D6, such as flecainide, vinblastine, carbamazepine, and tricyclic antidepressants. 

P450 system Concomitant use of TCAs with other drugs metabolized by cytochrome P450 2D6 may require lower doses than those usually prescribed for either the TCA or the other drug. 

Tr/azo/obenzocf/azep/nes-Triazolam and alprazolam, metabolized by cytochrome P-450 3A4, have increased plasma concentrations when administered concomitantly with nefazodone. If triazolam is coadministered with nefazodone, a 75% reduction in the initial triazolam dosage is recommended. It is recommended that triazolam not be used in combination with nefazodone. No dosage adjustment is required for nefazodone. 

Potential interaction with drugs that inhibit or are metabolized by cytochrome P-450 (3A4 and 2D6) isozymes Caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by the 3A4 isozyme (in particular, cisapride or pimozide). 

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. 

Metaboiism - Neither valacyclovir nor acyclovir metabolism is metabolized by cytochrome P450 enzymes. 

Metaboiism/Excretion - Delavirdine is extensively converted to several inactive metabolites. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The apparent plasma half-life of delavirdine increases with dose mean half-life following 400 mg 3 times daily is 5.8 hours (range, 2 to 11 hours). 

Blake MJ, Abdel-Rahman SM, Pearce RE, Leeder JS, Kearns GL. Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res 2006 60(6) 717-23. 

C. Histamine stimulates gastric acid secretion through an effect on Hj-receptors of gastric parietal cells. Although certain antihistamines are metabolized by cytochrome P450 enzymes, histamine does not induce their production. Histamine helps to maintain a wakeful state through an effect on Hj-receptors. Histamine-mediated hronchoconstriction is mediated by Hj-receptors, while histamine-mediated vasodilation occurs as a result of stimulation of Hi- and Hj-receptors. 

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