CYP1A2 isozymes

The amino amide-type local anesthetics, however, are metabolized primarily in the liver, involving CYP1A2 isozymes (49). A general metabolic scheme for lidocaine is shown in Figure 16.10. 

Lidocaine is extensively metabolized in the liver by N-dealkylation and aromatic hydroxylations catalyzed by CYP1A2 isozymes (Fig. 16.10). Lidocaine also possesses a weak inhibitory activity toward the CYP1A2 isozymes and, therefore, may interfere with metabolism of other medications (52). 

The metaboiism of ropivacaine in human is mediated by hepatic CYP1A2 isozymes and, to a minor extent, by CYP3A4 (50). The major metaboiite is 3-hydroxyropivacaine, and the minor metaboiite is (S)-2, 6 -pipecoioxyiidide (a N-deaikyiated product). 

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. 

Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon the CYP2C subfamily and CYP3A4 isozymes also are involved to a minor degree. 

Polybrominated Biphenyls. A recent study has used caffeine as a potential tool to characterize exposure and/or effect of PBBs (Lambert et al. 1990). In this test, caffeine is used as a metabolic probe of cytochrome P-450 isozymes activity from the CYPIA family, which in animals is significantly induced by PBBs (Safe 1984). Tire caffeine breath test (CBT) is primarily useful for detecting induction of CYP1A2 activity in human liver, and for that reason, it also has been used as a marker for exposure to PCBs, CDDs, and CDFs (Lambert et al. 1992). A volunteer population of 50 Michigan subjects with previously high serum PBB levels and 50 with undetectable or low serum levels was compared to a control population not exposed to PBBs (Lambert et al. 1992). Two tests were conducted, the CYP1A2-dependent caffeine... 

Ethanol and a number of other chemicals, including acetone and certain imidazoles, induce CYP2E1. Piperonyl butoxide, isosafrole, and other methylenedioxyphenyl compounds are known to induce CYP1A2 by a non-Ah receptor-dependent mechanism. Peroxisome proliferators, including the drug, clofibrate, and the herbicide synergist tridiphane induce a CYP4A isozyme that catalyzes the -oxidation of lauric acid. 

Substrate specificity is reflected in that each CYP isozyme requires different molecular features of its substrates. Thus, CYP2E metabolizes substrates with an alcohol or keto moiety. For CACs, CYP1A1, CYP1A2 and CYP2B are the most important isozymes. CYP1A metabolizes mostly planar substrates like 2,3,7,8-tetrachlorodibenzo-p-dioxin, whereas CYP2B transforms the more globular substrates, e.g. the transformation of the pesticide aldrin into dieldrin. 

Ciprofloxacin, given to a patient who had been successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression (73). This may have been due to inhibition of CYP1A2 and CYP3A4, two of the isozymes involved in the metabolism of methadone. 

Although long-term alcohol can induce some cytochrome P4S0 isozymes, such as CYPlAl, CYP1A2 (257), CYP2B1, and CYP2E1 (258), these effects are not relevant to the coumarins, which are mostly metabolized by CYP2C9. 

Acetylaminofluorene is biotransformed in the liver. 2-Acetylaminofluorene can stimulate cytochrome P450 lAl isozyme (CYPIAI) activity, inducing both CYPIAI and CYP1A2 proteins, whereas... 

Ryu, D.Y., Levi, P.E. and Hodgson, E. (1995). Regulation of cytochrome F450 isozymes CYPI Al, CYP1A2 and CYP2BI0 by three benzodioxoie compounds. Chem.-tiiot. Interact. 96, 235-247. 

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