Phase II metabolism enzymes

As inhibitors of certain enzyme reactions and apoptosis related to the development of cancer (Naasani et al, 1998 Yang et al, 2001), specifically by selective induction or modification of phase I and phase II metabolic enzymes so as to increase the formation and excretion of detoxified metabolites of carcinogens. 

Table 10.2 Expression profiles of phase II metabolic enzymes in human bronchial mucosa and in vitro cell culture models.

Table 11.3 Summary of the Expression Pattern and Activities of Phase I and Phase II Metabolic Enzymes and Various Peptidases/Proteases in Human Peripheral Lung Tissues, Primary Rat AEC Culture and Human Alveolar Epithelial Cell Line, A549.

Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. 2003. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice Possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol 92 33-38. 

IV. DRUG-DRUG INTERACTIONS WITH PHASE II METABOLIC ENZYMES THAT LEAD TO TOXICITIES... 

There are only a few published reports of serious toxicities caused by drugs as a result of drug-drug interactions with phase II metabolic enzymes. This in part may reflect less attention given to these enzymes and/or lesser extents of induction and inhibition of these enzymes by drugs (chap. 4). 

K. L. R. Integration of hepatic drug transporters and phase II metabolizing enzymes Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur. J. Pharm. Sci. 27, 447-486, 2006. 

Phase I metabolism Phase II metabolism Enzyme induction Enzyme inhibition OS enhancement Receptor interaction Endocrine disruption Immunosuppression Immunostimulation... 

These data led to the extensive clinical testing of droloxifene in stage IV breast cancer [306]. In a phase III trial for treatment of ER- and/or PR-positive advanced breast cancer, droloxifene was found to be significantly less effective than tamoxifen overall [307]. As might be anticipated for an agent that has rapid clearance because it is rapidly conjugated by phase II metabolizing enzymes [308, 309], doses of 60 mg daily were used in its clinical trials, and may explain why droloxifene was inferior to tamoxifen. Its further clinical development has therefore been stopped. 

The preclinical pharmacokinetics of protein pharmaceuticals is distinctively different from small-molecule drugs. The phase I and phase II metabolizing enzymes, for example, the cytochrome P450 and glucoronosyl transferases, which play dominant roles in the metabolism of small-molecule drugs, are not significantly involved in protein metabolism. Instead, because all protein pharmaceuticals invariably share a common polypeptide backbone, they are susceptible to proteolysis as a clearance mechanism. However, the disposition, pharmacokinetics. 

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