Biotransformation pathways phase

This section focuses on (1) a discussion of the overall process of biodegradation, (2) a review of the different types, aspects and phases of biodegradation of several classes of organic pollutants, (3) an examination of the environmental factors affecting biodegradation and biotransformation mechanisms, and (4) a description of the different biodegradation and biotransformation pathways. 

Xenobiotics are biotransformed by phase I enzymes and phase II conjugation reactions to form a variety of metabolites that are generally more water-soluble and less toxic than the parent compound. Occasionally, the enzymic action of phase I or II systems leads to the formation of unstable intermediates or reactive metabolites that are toxic or carcinogenic. Many physiological factors influence the rate of xenobiotic metabolism and the relative importance of different pathways of metabolic activation or detoxication. 

Microsomal oxidative reactions constitute the most prominent phase I biotransformation pathway for a wide variety of structurally unrelated drugs (Table 1.4). Some drugs (e.g. amphetamine, diazepam, propranolol, lignocaine) simultaneously undergo more than one type of microsomal-mediated oxidative reaction. Microsomal enzymes are located primarily in liver cells, where they are associated with the smooth-surface (without ribosomes) endoplasmic reticulum (Fouts, 1961). Lipid solubility is a prerequisite for drug access to the... 

Fish have active Phase I and Phase II biotransformation pathways that can modify the disposition and toxicity of pesticides. Although more studies are characterizing in vivo metabolites of pesticides in fish, there is still a significant lack of knowledge about the ultimate fate of these compounds in the fish. In addition, very little is known about the specific enzymes responsible for the formation of specific metabolites of various pesticides. For example, although multiple CYP isoforms have been identified in fish, the substrate specificities with regard to pesticides are unknown and deserve further study. 

A human ADME study conducted using radiolabeled form of the NCE (usually referred to as 14C-human ADME) is a study that in most cases is required prior to start of the Phase III clinical trials and the data from the human ADME study are important components of the nonclinical sections of the NDA submission and drug label. The objectives of 14C-human ADME studies are to determine the total disposition of the NCE, encompassing mass balance, routes of NCE/metabolite elimination, and biotransformation pathways. 

Goyer RA (1991) Toxic effect of metals. In Amdur MO, Doull J, Klaassen CD (eds) Casarett and Doull s toxicology, the basic science of poisons, 4th edn. McGraw-Hill Pergamon, New York, pp 623-680 Goyer RA, Cherian MG (1992) Role of metallothionein in human placenta and rats exposed to cadmium. In Nordberg GF, Herber RFM, Alessio L (eds) Cadmium in the human environment. I ARC, Lyon, pp 239-247 Gregus Z, Watkins JB, Thompson TN, Klaassen CD (1982) Resistance of some phase II biotransformation pathways to hepatotoxins. J Pharmacol Exp Ther 222 471-479... 

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. 

Two types of enzymatic pathways, the so-called phase I and phase II pathways, are generally implicated in drug biotransformation. Phase I pathways correspond to functionalization processes, whereas phase II correspond to biosynthetic or conjugative processes. Phase I functionalization processes include oxidation, reduction, hydrolysis, hydration, and isomerization reactions. 

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