Phase enzymes

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

The enzymes involved in the biotransformation of pollutants and other xenobiotics will now be described in more detail, starting with phase 1 enzymes and then moving on to phase 2 enzymes. 

TALALAY p, FAHEY J w, HOLTZCLAW w D, PRESTERA T and ZHANG Y (1995) Chemoprotection against cancer by phase 2 enzyme induction , Toxicol Lett, 82-3, 173-9. 

In some studies it has been shown that ITCs can cause increases in the pro-apoptotic caspase enzymes, caspase 3, caspase 8 or caspase However, in other work, specific caspase inhibitors failed to block cell death or cell detachment from the substratum . This suggests that caspase-activation may only be a bystander event, or may only occur after the initiating event of a block in the cell cycle. Indeed, although expression of c-Jun amino-terminal kinase (INK) in response to ITCs has been linked to the pro-apoptotic process, it remains entirely possible that this is a parallel signalling pathway, more closely related to the induction of Phase 1 or Phase 2 enzymes than to the... 

TALALAY p (1991) Chemical Protection Against Cancer by Inducation of Electrophile Detoxification (phase 2) Enzymes Cellular Molec Targets Chemoprev, 1-11. 

KIRLIN w G, CAi J, DELONG M J, PATTEN E J and JONES D P (1999) Dietary compoimds that induce cancer preventive phase 2 enzymes activate apoptosis at comparable doses in HT29 colon carcinoma cells , JNutr, 129 1827-35. 

Talalay, P. 2000. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 12(1—4) 5—11. 

Zhang, Y. and Talalay, P. (1998). Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic phase 2 enzymes, Cancer Res., 58, 4632-4639. 

Give an example of (a) a phase 1 enzyme (apart from cytochrome P-450) (b) a phase 2 enzyme, which can be induced. 

Moreover, the induction of phase 2 enzymes by curcumin is independent on AhR or CYP1A1, thus curcumin is classified as a monofunctional inducer [Dinkova-Kostova and Talalay, 1999]. 

Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. 2002. Direct evidence that sulfhydryl groups of Keapl are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99 11908-11913. 

In addition to their direct antioxidant activity, ferulic acid and its ester derivatives have also been shown to act as indirect antioxidants, that is, to induce cytoprotective (phase 2) enzymes [Dinkova-Kostova et al., 1998 Dinkova-Kostova, 2002], Similarly to curumin, ferulic acid derivatives also... 

Dinkova-Kostova AT, Abeygunawardana C, Talalay P. 1998. Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors Correlation of potencies as phase 2 enzyme inducers and radical scavengers. J Med Chem 41 5287-5296. 

Kensler TW, Curphey TJ, Maxiutenko Y, Roebuck BD. Chemoprotection by organosulfur inducers of phase 2 enzymes dithiolethiones and dithiins. Drug Metab Drug Interact 2000 17 3-22. 

Metabolic activation of chemical carcinogens by cytochrome P-450 is well-documented. In addition to the Phase 1 enzymes, Phase 2 enzymes such as GSH transferases can also participate in metabolically activating or inactivating (detoxification) chemical carcinogens. Human genetic polymorphisms have been characterized in some Phase 1 and Phase 2 genes (see Chapters 11 and 13). Such polymorphisms could alter an individual s susceptibility to cancer induced by certain chemical... 

The developmental patterns of both phase 1 and phase 2 enzymes have been extensively reviewed [22, 23]. 

Drug metabolism is impaired in patients with liver disease, with CYP-mediated reactions affected more than phase 2 enzymes [35]. Impairment of CYP expression and activity correlates with the severity of liver disease and also, for some of the enzymes, the aetiology of cirrhosis. 

The effects of liver cirrhosis on the phase 2 enzymes has recently been reviewed by Elbekai et al. [36]. 

Iqbal S, Vickers C, Elias E (1990) Drug metabolism in end-stage liver disease. In vitro activities of some phase 1 and phase 2 enzymes.) Hepatol 11 37-42. 

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