Metabolism bioactivation

An example of a structural substituent that is often metabolized (bioactivated) to an electrophile is the allyl alcohol substituent (C=C—C—OH). Allyl alcohol moieties are found in many commercial chemical substances, either as the free alcohol or as an ester or ether. As illustrated in Scheme 4.1, allyl alcohols (and also as their esters or ethers) that contain at least one hydrogen atom on the alcoholic carbon can be oxidized in the liver by alcohol dehydrogenase (ALDH) to the corresponding a, 3-unsaturated carbonyl metabolite, which is toxic in many cases [29-31]. The hepatotoxicity of allyl alcohol (1), for example, is due to its oxidation by ALDH to acrolein (2), an a,(3-unsaturated aldehyde, which undergoes Michael addition with cellular nucleophiles in the liver [29] (Scheme 4.1). Cyclic allyl alcohols (Scheme 4.1) are expected to undergo similar enzymatic oxidation to yield a,(3-unsaturatcd carbonyl metabolites and are also likely to be toxic. 

Tamoxifen could thus be considered a quasi-prodrug that requires metabolic bioactivation to exert its effects. The metabolism of tamoxifen is complex and undergoes extensive phase I and phase n transformation (Fig. 2). Various potentially... 

Pirmohamed M, Madden S, Park BK. Idiosyncratic drug reactions metabolic bioactivation as a pathogenic mechanism. Clin Pharmacokinet 1996 31 215-230. 

Figure 3.2 Comparison of metabolic bioactivation and biotoxification processes.

Fourth, certain segments of the nephron have a capacity for metabolic bioactivation. For example, the proximal and distal tubules contain isozymes of the cytochrome P450 monooxygenase system that may mediate intrarenal bioactivation of several protoxicants. Additionally, prostaglandin synthetase activity in medullary and papillary interstitial cells may be involved in cooxidation of protoxicants, resulting in selective papillary injury. 

Chloroform is a nephrotoxicant that most likely undergoes metabolic bioactivation within the kidney. Chloroform (CHC13), a common organic solvent widely used in the chemical industry, produces hepatic and renal injury in humans and experimental animals. Renal necrosis due to chloroform is sex- and species-specific For example, male mice exhibit primarily renal necrosis whereas female mice develop... 

It is instructive to examine which drugs are substrates for various isoforms of CYP enzymes. Table 11.2 lists some of the substrates for different CYP isoforms (10, 11). There are several examples of a single compound that is metabolized by multiple CYP enzymes (acetaminophen, diazepam, caffeine, halothane, warfarin, testosterone, zidovudine), and CYP enzymes that metabolize bioactive endogenous molecules (prostaglandins, steroids) as well as drugs. 

Virtual predictions of metabolic (bioactivation) sites in molecules. The in silico tool MetaSite can identify the "most likely" sites of P450-mediated... 

The human esophagus is a target organ for cancer, and this has potentiated searches for metabolic bioactivators of tobacco-smoke carcinogens in the organ. Human... 

Metabolic Bioactivation Reactions Potentially Related to Drug Toxicities... 

The discussion that follows focuses on selected examples of metabolic transformations that may be linked to the formation of potentially neurotoxic metabolites. Although the number of well-characterized examples of such biotransformations is relatively few, it may be reasonable to speculate that the neurological disorders associated with long-term exposure to substances of abuse and some behaviormodifying medications may involve biochemical lesions mediated by chemically reactive metabolites. Thus, it may be important when attempting to assess the possible significance of metabolic bioactivation processes to appreciate that the chemical instability of reactive metabolites which can make the identification and characterization of their biological properties difficult. 

Mechanisms such as induction of microsomal cytochrome P-450 by chlordecone, whereby enhanced metabolic bioactivation of CCl could be invoked, and enhanced lipid peroxidation are inadequate to explain the remarkably powerful potentiation of toxicity and lethality. Treatment with phenobarbital, which results in a 3-... 

Prepn of the diacetate Johnson el al, J. Chem. Soc. 1954, 1302. Crystal structure Haner, Norton. Acta Crysl. 16, 707 (1963). Review of metabolism, bioactivity and assay during pregnancy P. J. Keller. Coni rib Gynecol Obstet. 2, 73-91 0976). 

Metabolic Bioactivation Role in Hepatotoxicity, Idiosyncratic Reactions, and Chemical Carcinogenesis... 

Kinobe RT, Parkinson OT, Mitchell DJ, et al. P450 2C18 catalyzes the metabolic bioactivation of phenytoin. Chem Res Toxicol 2005 18 1868-1875. 

Castagnoli N Jr, Rimoldi JM, Bloomquist J, et al. Potential metabolic bioactivation pathways involving oyolio tertiary amines and aza-arenes. Chem Res Toxicol 1997 10 924-940. 

I. Mechanism of toxicity. Carbon tetrachloride and chloroform are CNS depressants and potent hepatic and renal toxins. They may also increase the sensitivity of the myocardium to arrhythmogenic effects of catecholamines. The mechanism of hepatic and renal toxicity is thought to be a result of a toxic free-radical intermediate of cytochrome P-450 metabolism. (Bioactivation of CCI4 has become a model for chemical toxicity induced by free radicals.) Chronic use of metabolic enzyme inducers such as phenobarbital and ethanol increases the toxicity of carbon tetrachloride. Carbon tetrachloride is a known animal and suspected human carcinogen. Chloroform is embryotoxic and an animal carcincogen. 

There are many reviews dealing with the impact of physicochemical properties on off-target behavior, for example, toxicity of compounds due to structural and electronic makeup [5] as well as metabolic bioactivation [51]. With these reviews in hand, it is reasonable to assess the quality of a cluster based on peer literature. However, it is much better to assess the cluster quality using real data from com-poimds with high similarity to the compounds of the cluster. 

Castagnoh, N., Jr., J. Rimoldi, J. Bloomquist, and K.P. Castagnoh. 1997. Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes. Chem Res Toxicol 10 924-940. 

The body uses metaboUc processes to transform toxic chemicals to more hydrophilic, thus more easily excreted, compounds. In some cases, however, metabolism bioactivates a molecule, increasing its toxicity. MetaboUsm can be broken into two main phases. In phase I, a functional chemical group is added to the chemical compound in preparation for phase n. Phase I enzymes can oxidize, reduce, or hydrolyze... 

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