CYP1A1 isozymes

Owing to the fact that ethyl ethers are especially effective substrates for CYP1A1 [184], the probe possesses an ethyl group on the phenolic oxygen of the trimethyl lock. In vitro, fluorescence was manifested by CYP1A1 isozyme with Kcat/KM 8.8 x 103 M-1s 1 and KM 0.09 pM. In cellulo, the probe revealed the induction of cytochrome P450 activity by the carcinogen 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD), and its repression by the chemoprotectant resveratrol. 

MultiCASE) (Dearden et al., 1997 Klopman and Rosenkranz, 1994). A further system is Computerized Optimized Parametric Analysis of Chemical Toxicity (COMPACT) (Lewis et al., 1994). The latter analyses the ability of a molecule to fit into the active site of the CYP1A1 isozyme of cytochrome P450 (CYP) (and some other CYP isozymes), by modeling molecular shape (planarity or area/depth) and chemical reactivity (covalent bond formation). The use of COMPACT is limited to molecules that are activated by these CYP enzymes. 

An example of the second type of chiral effect in metabolism is afforded by benzofa]-pyrene, also discussed in more detail in chapter 7. This carcinogenic polycyclic hydrocarbon is metabolized stereos elec lively by a particular cytochrome P-450 isozyme, CYP1A1, to the (+)-7R,8S oxide (chap. 7, Fig. 5.2), which in turn is metabolized by epoxide hydrolase to the (—)-7R,8S dihydrodiol. This metabolite is further metabolized to (- -)-benzo[aIpyrene, 7R,8S dihydrodiol, 9S,10R epoxide in which the hydroxyl group and epoxide are trans and which is more mutagenic than other enantiomers. The (—)-7R,8S dihydrodiol of benzo[aIpyrene is 10 times more tumorigenic than the (+)-7R,8S enantiomer. It was reported that in this case the configuration was more important for tumorigenicity than the chemical reactivity. 

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. 

Certain PCDDs and PCDFs act as very powerful inducers of the MFO system and give rise to de novo synthesis of CYP1A1, a cytochrome P450 isozyme associated with aryl hydrocarbon hydrolase (AHH or Ah), and ethoxyresorufin O-deethylase (EROD), a common biomarker for PCDD exposure. 

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