Xenobiotic metabolites

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Hubl, U. and Stevenson, D.E. (2001) In vitro enzymic synthesis of mammalian liver xenobiotic metabolites catalyzed by ovine liver microsomal cytochrome P450. Enzyme and Microbial Technology, 29, 306-311. 

Straub, K. M. Rudewicz, P. Garvie, C. 1987. Metabolic mapping of drugs rapid screening techniques for xenobiotic metabolites with m.s./m.s. techniques. Xenobiotica,17, 413-422. 

A disadvantage to measuring toluene exposure by hippuric acid is the production of this metabolite from natural sources, and the determination of toluylmercapturic acid is now favored as a biomarker of toluene exposure.10 An interesting sidelight is that dietary habits can cause uncertainties in the measurement of xenobiotic metabolites. An example of this is the measurement of worker exposure to 3-chloropropene by the production of allylmercapturic acid.11 This metabolite is also produced by garlic, and garlic consumption by workers was found to be a confounding factor in the method. Thiocyanate monitored as evidence of exposure to cyanide is increased markedly by the consumption of cooked cassava. 

Some metabolic conjugative processes result in the production of lipophilic derivatives that are not readily eliminated. While their physical properties are different from the classical hydrophilic conjugates, the mechanism of formation clearly defines them as conjugates (i.e., they are formed as the result of a union of xenobiotic metabolites with endogenous molecules). The reactions involve the coupling of xenobiotic acids and alcohols with endogenous intermediates of lipid synthesis (i. e., the acids with glycerol and cholesterol and the alcohols with the fatty acids). 

With lipophilic conjugation, the xenobiotic metabolites appear to be incorporated in the lipid biosynthetic pathway similar to the normal constituents. One would expect the conjugates to have turnover times similar to that of their natural counterparts. Whether the lipophilic conjugates have any deleterious effect on the organism would depend upon the type and amount of bioactivity retained by the metabolites before and after conjugation. 

Transcription is activated by xenobiotic metabolites and oxidative stress. 

Nicholson, J.K., Lindon, J.C., Scarfe, G., Wilson, I.D., Abou-Shakra, F., Castro-Perez, J., Eaton, A., Preece, S. High-performance liquid chromatography and inductively coupled plasma mass spectrometry (HPLC ICP MS) for the analysis of xenobiotic metabolites in rat urine application to the metabolites of 4-bromoaniline. Analyst 125, 235-236 (2000)... 

Not all xenobiotic metabolites are readily eliminated from the body. Some of the conjugates produced in Phase II metabolism have lipophilic character and are included in the biosynthesis of body lipids. These can be retained in the body and have delayed toxic effects. 

Though the toxicity of xenobiotics is generally decreased by metabolism, some xenobiotic metabolites are more toxic than their parent compounds. As noted earlier, the metabolite of benzo (a) pyrene is a lung carcinogen. Similarly, it is the metabolite of 1-naphthylamine and not the parent compound that is a bladder carcinogen. 

Phase I Reaction Class of Xenobiotic Metabolite Susceptible to Glucoside Conjugation... 

During the recent years several reviews on the analytical methodology and strategy involved in isolating xenobiotic metabolites, including conjugates have been published,... 

Table I. Xenobiotics or xenobiotic metabolites (aglycones) used In...

Table II. Xenoblotlcs or xenobiotic metabolites (aglyconea) used...

As illustrated in Fig. 1, methionine synthase is positioned at the intersection between transsulfuration and methylation pathways. As a consequence, its level of activity exerts control over cellular redox status, since it determines the proportion of HCY that will be diverted toward cysteine and GSH synthesis. Methionine synthase activity is exceptionally sensitive to inhibition during oxidative stress, primarily because its cobalamin cofactor is easily oxidized (Liptak and Brunold, 2006). This allows methionine synthase to serve as a redox sensor, lowering its activity whenever the level of oxidation increases, until increased GSH synthesis brings the system back into balance. Electrophilic compounds, such as oxygen-containing xenobiotic metabolites, also react with cobalamin, inactivating the enzyme and increasing diversion of HCY toward GSH synthesis (Watson et al., 2004). Thus, methionine synthase is a sensor of both redox and xenobiotic status. 

The role of metabolism in the wider context of the detoxification and elimination of xenobiotics from biota is discussed in Chapter 7, Section 7.5, and its potential role in the dissemination of xenobiotic metabolites in Section 3.5. 

Type of conjugation Endogenous substance Transferring enzyme and location Type of xenobiotics metabolites conjugated... 

Toxic or reactive xenobiotic metabolites are detected by measuring alkylation or covalent binding of endogenous macromolecules. 

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