Cytochrome P450 inducers

Ong. T., Mukhtar, M., Wolf, C.R. and Zeiger, E. (1980). Differential effects of cytochrome P450-inducers on promutagen activation capabilities and enzymatic activities of S-9 from rat liver. J. Environ. Pathol. Toxicol. 4 55-65. 

Hepatic necrosis can be classified by the zone of the liver tissue affected. Xenobiotics, such as acetaminophen or chloroform, that undergo bioactivation to toxic intermediates cause necrosis of the cells surrounding the central veins (centrilobular) because the components of the cytochrome P450 system are found in those cells in abundance. At higher doses or in the presence of agents that increase the synthesis of cytochrome P450 (inducers), the area of necrosis may incorporate the... 

Vignette 5.3 Blood Concentration of Substrate Is Reduced by Cytochrome P450 Inducer... 

Quetiapine is metabolized by hepatic CYP 3A3/4. Concurrent administration of cytochrome P450-inducing drugs, such as carbamazepine, decreases blood levels of quetiapine. In such circumstances, increased doses of quetiapine are appropriate. Quetiapine does not appreciably affect the pharmacokinetics of other medications. Pharmacodynamic effects are expected if quetiapine is combined with medications that also have antihistaminic or a-adrenergic side effects. Because of its potential for inducing hypotension, quetiapine also may enhance the effects of certain antihypertensive agents. 

Cytochrome P450 inducer (oral contraceptive failure) Autoinduction Rare blood cell dyscrasias aplastic anemia, agranulocytosis Hepatotoxicity Rash risk, including Stevens-Johnson syndrome Risk for SIADH Teratogenicity risk neural tube defects, craniofacial defects... 

Li AP, Hartman NR, Lu C, et al. Effects of cytochrome P450 inducers on 17alpha-ethinyloestradiol (EE2) conjugation by primary human hepatocytes. Br J Clin Pharmacol 1999 48 733-742. 

There are basically three types of cytochrome P450 inducers (1) phenobarbital-like (the major class) (2) methylcholanthrene-like (which actually increases a P448 isozyme) and (3) anabolic steroids. The former two have been the most frequently studied. Research over the past 40-50 years indicates that their mechanism of action involves genetic interaction, possibly via derepression of a repressor gene, and the subsequent synthesis of mRNA for the specific enzyme proteins. Examples of phenobarbital-like enzyme inducers, the most common, are shown in Table 3.6. 

In the fall army worm, Spodopterafrugiperda, sulfoxidation of phorate requires NADPH. It is inhibited by carbon monoxide and piperonyl butoxide, and induced by cytochrome P450 inducers (e.g., indole 3-carbinol and indole 3-acetonitrile) (Yu, 1985). 

Villikka K, Kivisto KT, Maenpaa H, Joensuu H, Neuvonen PJ. Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors. Clin Pharmacol Ther 1999 66(6) 589-93. 

Ryan DE, Ramanathan L, Iida S, Thomas PE, Haniu M, Shively JE, Lieber CS, Levin W. 1985. Characterization of a major form of rat hepatic microsomal cytochrome P450 induced by isoniazid. J. Biol. Chem. 260 6385-93... 

Phenytoin and carbamazepine have been reported to decrease haloperidol serum levels by about 50% due to their hepatic cytochrome P450-inducing properties. Preliminary data suggest that haloperidol can lower valproate serum levels. 

These can decrease clozapine serum levels by about 60% (carbamazepine) and 85% (phenytoin) due to hepatic cytochrome P450-inducing properties. Plasma concentrations of clozapine and its metabolites have been reported to be either slightly decreased or increased when combined with valproate. 

Meneses-Lorente G, de Longueville F, Dos Santos-Mendes S (2003). An evaluation of a low-density DNA microarray using cytochrome P450 inducers. Chem. Res. Toxicol. 16 1070-1077. 

The cytochrome P450 inducers phenobarbital and beta-naphthoflavone slightly inhibited the growth of C. roseus suspension cultures. Phenobarbital increased serpentine accumulation in cells in a production medium, but not in cells grown in a normal B5-growth medium. The cytochrome P450 inhibitor ketoconazole was found to inhibit serpentine production (114). No measurements of GlOH activities were performed. 

Dostalek M, Brooks JD, Hardy KD, Milne GL, Moore MM, Sharma S, Morrow JD, Guengerich FP (2007) In vivo oxidative damage in rats is associated with barbiturate response but not other cytochrome P450 inducers. Mol Pharmacol 72 1419-1424... 

Fourth, the rat premedication of P-carotene (2) with two cytochrome P450 inducers such as pentobarbital (32) and P-naphthoflavone (33) (Figure 6) could increase the enzyme activity of the intestional P,P-carotene 15,15 -monooxygenase up to 39%. 

Halwachs, S., Kneuer, C., and Honscha, W., 2007. Downregulation of the reduced folate carrier transport activity by phenobarbital-type cytochrome P450 inducers and protein kinase C activators. Biochimica et Biophysica Acta. 1768 1671-1679. 

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