Phase II enzymes

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

There is ample evidence from both animal experiments and tissue cultures studies to show that brassica vegetables and their constituents selectively induce Phase II enzymes. Evidence for the induction of Phase II enzymes by... 

Wettasinghe, M. et al.. Phase II enzyme-inducing and antioxidant activities of beetroot Beta vulgaris L.) extracts from phenotypes of different pigmentation, J. Agric. Food Chem., 50, 6704, 2002. 

Wettasinghe, M. et al.. Screening for phase II enzyme-indncing and antioxidant activities of common vegetables, J. Food Sci., 67, 2583, 2002. 

Lee, C.-H. et al., Betalains, phase II enzyme-indncing components from red beetroot (Beta vulgaris L.) extracts, Nutr. Cancer, 53, 91, 2005. 

Induction of phase II enzymes, which conjugate reactive electrophiles and act as indirect antioxidants, appears to be the means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part,... 

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

Petri, N., Tannergren, C., Bennett, R. N., Holst, B., Bao, Y. et al., Intestinal absorption and metabolism of sulforaphane and quercetin as well as regulation of phase II enzymes in human jejunum in vivo and in Caco-2 cells, Drug Metab. Dispos. 2003 (in press). 

It has now been established that genetic polymorphisms in drug metabolizing enzymes such as the cytochrome P450s (CYP) and the phase II enzyme, thiopu-rine methyltransferase, are responsible for inter-individual variability in response and adverse reactions [12, 13]. However, at the present time, the impact of poly-... 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

In addition to phase I and phase II enzymes, equally important is a group of transporter proteins expressed in various tissues, such as the liver, intestine, brain and kidney, which modulate the absorption, distribution and excretion of many drugs. 

The cytosolic SULTs are another important family of phase II enzymes that catalyze the conjugation of nucleophilic compounds. SULTs catalyze the transfer of a sulfonyl... 

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