Xenobiotic metabolism reduction

Because xenobiotic metabolism involves many enzymes with different cofactor requirements, prosthetic groups, or endogenous cosubstrates, it is apparent that many different nutrients are involved in their function and maintenance. Determination of the effects of deficiencies, however, is more complex because reductions in activity of any particular enzyme will be effective only if it affects a change in a rate-limiting step in a process. In the case of multiple deficiencies, the nature of the rate-limiting step may change with time... 

Fig. 3.2 Biological abstraction. Yeast cells reflect anaerobic, reductive metabolism (intestine) as well as aerobic, oxidative metabolism (liver), if glycolysis is regarded as the most active pathway. Therefore, the yeast Saccharomyces cerevisiae is a good model organism for studies of xenobiotic metabolism.

Examples of oxidative reactions are shown in Table 3.3. Generally, reduction and hydrolysis reactions play subordinate roles in xenobiotic metabolism compared to oxidation reactions. Examples of reduction and hydrolysis reactions are shown in Tables 3.4 and 3.5, respectively. To reiterate the net result of phase I reactions is the... 

Metabolic pathways such as the electron transport chain of mitochondrial respiration and biochemical reduction of oxygen by enzymes of xenobiotic metabolism,... 

The process of xenobiotic metabolism contains two phases commonly known as Phase I and Phase II. The major reactions included in Phase I are oxidation, reduction, and hydrolysis, as shown in Figure 10.1. Among the representative oxidation reactions are hydroxylation, dealkylation, deamination, and sulfoxide formation, whereas reduction reactions include azo reduction and addition of hydrogen. Such reactions as splitting of ester and amide bonds are common in hydrolysis. During Phase I, a chemical may acquire a reaction group such as OH, NH2, COOH, or SH. 

The liver is the principal organ responsible for xenobiotic metabolism. One of its major roles is to convert lipophilic nonpolar molecules to more polar water-soluble forms. The drug molecule (a xenobiotic) can be modified by phase I reactions, which alter chemical structure by oxidation, reduction, or hydrolysis or by phase II reactions, which conjugate the drug (glucuronidation or sulfation) to create more water-soluble forms. Typically, both phase I and phase II reactions occur. Most drug metaboHsm takes place in the microsomal fraction of the hepatocytes, where many environmental chemicals and endogenous biochemicals (xeno-biotics) are also processed by the same mechanisms. 

Those include C-, N- and 5-oxidations, N-, 0- and 5-deaIkylation, deaminations, and certain dehalogenations. Under anaerobic conditions, it can also catalyze reductive reactions. The CYP monooxygenase system is a multien-zymatic complex constituted by the CYP hemoprotein, the flavoprotein enzyme NADPH CYP reductase, and the unsatnrated phospholipid phosphatidylcholine. The isoforms involved in xenobiotic metabolism are membrane bonnd enzymes situated in the endoplasmic reticnlnm. After... 

The pathways ot xenobiotic metabolism are divided into two major categories. Phase 1 reactions (biotranstormations) include oxidation, hydroxylation, reduction, and hydrolysis. In these enzymatic reactions, a new functional group Is Introduced Into the substrate molecule, an existing functional group is modified, or a functional group or acceptor site tor Phase 2 transfer reactions Is exposed, thus making the xenobiotic more polar and, therefore, more readily excreted. 

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to a reduction in hepatic microsomal protein and lipid deficiency oxidative metabolism is decreased because of an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body. 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

In phase 1, the pollutant is converted into a more water-soluble metabolites, by oxidation, hydrolysis, hydration, or reduction. Usually, phase 1 metabolism introduces one or more hydroxyl groups. In phase 2, a water-soluble endogenous species (usually an anion) is attached to the metabolite— very commonly through a hydroxyl group introduced during phase 1. Although this scheme describes the course of most biotransformations of lipophilic xenobiotics, there can be departures from it. 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

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