Lipophilic xenobiotics metabolism

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. 

Vertebrate liver is a very rich source of enzymes that metabolize lipophilic xenobiotics, and subcellular fractions are prepared to study metabolism. Sometimes, other tissues such as brain, kidney, testis, and ovary are also treated in this way. A typical subcellular fractionation of liver might be as follows ... 

Looking at the foregoing results overall, the rates of loss in vivo are related to the rates of metabolism in vitro, measured or estimated. As with the OC insecticides, problems of persistence are associated with compounds that are not readily metabolized, for example, 2,2, 4,4, 5,5 -HCB in the foregoing examples. For further discussion of the dependence of elimination of lipophilic xenobiotics on metabolism, see Walker (1981). 

Virtually all organisms possess biotransformation or detoxification enzymes that convert lipophilic xenobiotics to water-soluble and excretable metabolites (Yu et al. 1995). In the metabolic process, PAHs are altered by Phase I metabolism into various products such as epoxides, phenols,... 

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

The cytochrome P450 system is the principal enzyme system for the metabolism of lipophilic xenobiotics. It is a heme-containing, membrane-bound, multi-enzyme system which is present in many tissues in vivo but is present at the highest level in liver. A coenzyme, cytochrome P450 NADPH oxidoreductase (OR), is essential for P450 catalytic function and cytochrome bs may stimulate catalytic activities of some enzymes. In human liver, it is estimated that there are 15-20 different xenobiotic-metabolizing cytochrome P450 forms. A standard nomenclature, based on relatedness of the amino acid sequences, has been developed (Nelson et al., 1993). The most recent... 

Comparative biochemistry. Some researchers believe that the proper role of comparative biochemistry is to put evolution on a molecular basis, and that detoxication enzymes, like other enzymes, are suitable subjects for study. Xenobiotic-metabolizing enzymes were probably essential in the early stages of animal evolution because secondary plant products, even those of low toxicity, are frequently lipophilic and as a consequence would, in the absence of such enzymes, accumulate in lipid membranes and lipid depots. The evolution of cytochrome P450 isoforms, with more than 2000 isoform cDNA sequences known, is proving a useful tool for the study of biochemical evolution. 

The following discussion will center on mixed-function oxidases involving the hemoprotein cytochrome P-450, the active center of which consists of protoporphyrin IX. Mixed-function oxidases based on cytochrome P-450 are perhaps best known for their role in the primary metabolism of lipophilic xenobiotics in mammals, birds, fish and many invertebrates including insects. While this function is often critical in determining the survival of an organism... 

The general strategy of xenobiotic metabolism (the metabolism of foreign compounds) is to convert lipophilic compounds into more readily excreted polar products. The rate of this metabolism is an important determinant of the duration and intensity of the pharmacological action of drugs. Drug metabolism can result in either toxication or detoxication. While both do occur, the major metabolites of most drugs are detoxication products. 

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases. Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic-metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences. 

Microsomes isolated from hepatic tissue appear to retain all of the mixed-function oxidase capabilities of intact hepa-tocytes because of this, microsomal preparations (with the necessary cofactors, e.g.. NADPH. Mg- ) are u.scd frequently for in vitro drug metabolism studies. Because of its membrane-bound nature, the cytochrome P-450 monooxy-gena.se system appears to be housed in a lipoidal environment. This may explain, in part, why lipophilic xenobiotics arc generally good sub.straics for the monooxygenase system. ... 

The major purpose of biotransformation is to chemically modify (metabolize) poorly excretable lipophilic compounds to more hydrophilic chemicals that are readily excreted in urine and/or bile. Without metabolism, lipophilic xenobiotics accumulate in biota, increasing the potential for toxicity. Examples of such compounds are highly halogenated polychlorinated biphenyls (PCBs) and polychlorinated dibenzofu-rans (TCDD and dioxins) that occur as tissue residues in humans. On the contrary, biotransformation is normally not required for xenobiotics with high water solubility because of rapid excretion in urine. 

Oxidation is the most common metabolic reaction for lipophilic xenobiotic and endobiotic compounds, in part because most mammalian tissues are well oxygenated. 

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. 

While it might he sjttculated that a similar biphasic ctlcct on metabolism could occur whenever a lipophilic xenobiotic capable of forming a stable inhibitory complex is administered, lew cases have been well documented. Even in the case of MDP interactions, the isoform spec if icily of cither inhibition or induction has not been well defined. Since both detoxification and activation of chemicals are. to a greater or lesser extent, isoform-sped lie, more recent studies have focused on clarifying which iso forms of P450 arc involved and the importance of these isoforms in the biphasic response (Lewandow ski ei a .. 

Interest In the phylogenetic aspects of xenobiotic metabolizing enzymes has motivated several Investigators to study xenobiotic conjugation In aquatic animals. In addition, evidence of extensive chemical pollution of some bodies of water which results In the exposure of aquatic animals to xenobiotics has provided a practical reason to study the ability of aquatic animals to biotransform lipophilic foreign chemicals to more polar metabolites which should be more readily excreted. 

I) metabolism of xenobiotics, insects also possess a variety of conjugation (phase II) mechanisms that catalyze the all-important final step in the conversion of lipophilic xenobiotics to polar, water-soluble, readily-excretable products (3-6). 

It is reasonable to speculate that highly lipophilic xenobiotics of limited solubility require carrier proteins to facilitate their mobilization, metabolism, and... 

Even if their absorption is high, the bioavailability of many compounds may be limited by an extensive metabolism that can affect the in vivo activity profile irrespective of its route of administration. Metabolism is vital since it transforms absorbed nutrients into endogenous substances required to maintain body functions for xenobiotics, including phytochemicals, metabolism represents the key body defence mechanism that converts them into less harmful, water-soluble, and thus excretable, compounds. Lipophilic, low molecular weight xenobiotics that are readily absorbed and distributed are difficult to eliminate and thus may accumulate to hazardous levels. Therefore, most lipophilic xenobiotics are metabolized into hydrophilic conjugates that are less likely to pass through membranes and, hence, can be more easily eliminated via the kidney. 

Two more factors contributing to the persistence of xenobiotics in polychaetes, molluscs, crustaceans and echinoderms, and presumably other marine invertebrates, are the formation of macromolecular adducts and the slow release of free metabolites. The incorporation of PAH into more stable compartments , possibly as a result of cytochrome P-450-mediated adduct formation, is particularly evident in molluscs (see Fig. 3). The metabolites of many xenobiotics are lost more slowly than the parent compound, resulting in a build-up in the tissues during both exposure and subsequent depuration periods. The primary function of metabolism, therefore, appears to be detoxication, by preventing the formation of specific reactive metabolites and, probably more importantly, the non-specific toxic action of lipophilic xenobiotics caused by their penetration of membrane systems. Loss of metabolites down a concentration gradient occurs, reducing body burden of the xenobiotic, but is obviously limited by the absence or ineffectiveness of specific transport and excretory systems for the polar metabolites. 

The answer is 3 [Chapter 3 III A 1 bj. Conjugation is the final step in xenobiotic metabolism. Endogenous molecules, such as glucuronide, sulfate, or glutathione, combine with activated molecules from phase I metabolism, forming products that are generally less lipophilic, more water soluble, and more... 

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