Excretion metabolites

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,... 

Crawford MJ, Croucher A, Hutson DH (1981) The metabolism of the pyrethroid insecticide cypermethrin in rats excreted metabolites. Pestic Sci 12 399—411... 

Kidney Failure The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH]... 

Excreted metabolites are collected on the resin column as a result of both static and steady-state exposures, and their separation is accomplished by thin-layer, gas-liquid, and/or high-pressure liquid chromatography of the eluted residue (Step 4). 

D. Reichert, H. W. Werner, M. Metzler, D. Henschler, Molecular Mechanism of 1,1-Dichloroethylene Toxicity Excreted Metabolites Reveal Different Pathways of Reactive Intermediates , Arch. Toxicol. 1979, 42, 159 - 169. 

Figure 2.12 Metabolic activation by the liver of pyrrolizidine alkaloid to the toxic pyrrole (liver bound and highly toxic) and the glutathione conjugate (excretion metabolite).

Despite this clearly outlined procedure, scientific progress in the field has been slow, as very few authors have as yet attempted environmental risk assessment of PhCs in water, focussing their attention, furthermore, mainly on parent compounds rather than their metabolites, on the effects of individual substances rather than mixtures on target organisms and on acute rather than chronic toxicity. In particular, metabolite analysis tended to be disregarded as their exposure is very difficult to assess due to a lack of consensus in the literature regarding excreted metabolite fractions moreover, analysis has shown that their relative contribution to the overall risk is typically low [99]. 

The importance of the gut microflora in the metabolism of isoflavones has been demonstrated. Antibiotic administration blocks isoflavone metabolism and germfree animals do not excrete metabolites. Moreover, only germfree rats colonized with microflora from a good equol producer excrete equol when fed soy. ... 

The synthesis of adrenal steroids and major excreted metabolites is illustrated in Fig. 5.3.1. Little secreted steroid product is excreted unchanged and most of the catabolism takes place in the liver, although cortisol metabolism by the kidney is clinically important and microbial metabolism in the gut can be quantitatively significant. The major metabolic transformations of hormonal steroids and precursors are detailed by Makin [54] and summarized in Fig. 5.3.2. GC-MS steroid profiling is the technique of choice for measurement of important urinary constituents. 

In the biotransformation of foreign compounds, the body attempts to convert such lipophilic substances into more polar, and consequently, more readily excreted metabolites. 

Glucuronidation. Complexation of the steroid to glucuronic acid, most predominandy via the C-3 hydroxyl, leads to a considerable portion of the excreted metabolites of all glucocorticoids. In infants, sulfurylation (formation of a sulfate ester) is also predominant (16). 

Animals Source Administration Dose mg/kg Blood or Seram or Plasma Metabolites (Concentration) Urinary excretion % Metabolites Time (h) Reference... 

A good example of the importance of tissue availability of the conjugating chemical is found with acetaminophen. At normal therapeutic doses, acetaminophen is safe, but can be hepatotoxic at high doses. The major portion of acetaminophen is conjugated with either sulfate or glucuronic acid to form water-soluble, readily excreted metabolites and only small amounts of the reactive intermediate, believed to be quinoneimine, are formed by the CYP enzymes (Figure 8.6). 

Methylation detoxifies a drug but produces a less polar and so less easily excreted metabolite. 

Biotransformation An enzymatic chemical alteration of a substance within the body that generally leads to a more excretable metabolite, sometimes producing a more toxic form of the xenobiotic. 

Animals. More than 90% excreted in urine and feces within 48 hr the major excreted metabolite was the O-desmethyl derivative. 

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. 

The term biotransformation is defined as biochemical changes in a substance through autometabolic processes. In this way, lipophilic substances can be converted into water-soluble (= excretable) metabolites in the liver. 

Metabolic epoxidation of carbon-carbon double bonds in alkenes and arenes is a fundamentally important biotransformation of foreign compounds. The primary epoxide (oxirane) metabolites formed generally undergo further biotransformation to more polar and readily excreted metabolites via conjugation with glutathione or epoxide-hydrolase-mediated hydrolysis to diols. Thus, epoxidation can be considered the first step in a metabolic detoxification scheme. On the other hand, epoxidation is also a... 

Metabolites derived by loss of an alkyl or arylalkyl group from ethers [Eq. (4)], thioethers [Eq. (5)], amines [Eq. (6)], and amides [Eq. (7)] represent common biotransformation pathways (R, R" = H, alkyl or aryl). These processes involve oxidation on carbon adjacent to the heteroatom. The intermediates are generally unstable and readily decompose to the corresponding alcohol, thiol, amine, or amide and an aldehyde. Intermediates formed from amides [Eq. (7)] are more stable and may be detected as excreted metabolites. If a secondary carbon atom is adjacent to the heteroatom, then this portion of the molecule is released as a ketone. The heteroatom may also be located in a cyclic structure (e.g., morpholine, piperazine). Two processes have been adopted for amines, namely, N-dealkylation or deamination, that are essentially the same event. In general, which of the two terms applies depends on the... 

Oxidation of divalent sulfur atoms in thioethers is a common biotransformation of sulfur-containing compounds [Eq. (9)]. Oxidation proceeds in two stages, first to the sulfoxide and then to the sulfone. Sulfoxides have increased polarity and are often observed as excreted metabolites, but they can also be reduced back to the sulfide. Formation of the sulfoxide creates an asymmetric center, and stereospecific oxidation can occur. Sulfones tend to be terminal metabolites no evidence for their reduction exists. 

Thus administration of an aldehyde invariably results in the appearance of the corresponding acid as an excreted metabolite, although in some instances both the acid and alcohol are formed. Thus the aldehyde formed by deamination of the antihistamine chlorpheniramine is metabolized to a mixture of the corresponding acid and alcohol. 

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