Bioactivation pathways

Kalgutkar, A.S., Gardner, I., Obach, R.S. et al. (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Current Drug Metabolism, 6, 161-225. 

The metabolism of 77-hexane takes place in the liver. The initial reaction is oxidation by cytochrome P-450 isozymes to hexanols, predominantly 2-hexanol. Further reactions convert 2-hexanol to 2-hexanone, 2,5-hexanediol, 5-hydroxy-2-hexanone, 4,5-dihydroxy-2-hexanone and the neurotoxicant 2,5-hexanedione. Hydroxylation at the 1- and 3- positions can be considered detoxification pathways hydroxylation at the 2- position is a bioactivation pathway. A diagram of the proposed pathway for mammalian metabolism of -hexane is presented in Figure 2-3. 

With the methylated PAHs, another bioactivation pathway leading to benzylic carbocations becomes available through side chain oxidation to form a benzylic alcohol, followed by esterification and solvolysis. Thus, benzylic sulfate ester formation (via initial formation of benzyl alcohol) constitutes an additional route that could contribute to metabolic activation (Fig. 2). ... 

A comprehensive listing of bioactivation pathways of organic fimctional... 

Scheme 15.1 Postulated bioactivation pathways of the anticonvulsant agent felbamate rational chemical approach to circumvent bioactivation by fluorofelbamate.

Scheme 15.2 Parallel detoxication pathways that compete with the P450-catalyzed bioactivation pathway of the antidepressant paroxetine as explanation for its wide safety margin.

To circumvent this bioactivation pathway, a more easily oxidizable C-H bond can be included in the molecule, such as a benzylic methyl group. Thus, toluene, is significantly less toxic than benzene since its major CYP metabolite is benzyl alcohol, which is converted to benzoic acid by ALDH. Benzoic acid is conjugated with glycine and eliminated in the urine as hippuric acid, which is much less toxic than the metabolites of benzene... 

Weber, G.L., Steenwyk, R.C., Nelson, S.D. Pearson, PG. (1995) Identification of V-acetyl-cysteine conjugates of l,2-dibromo-3-chloropropane evidence for cytochrome P450 and glutathione mediated bioactivation pathways. Chem. Res. Toxicol., 8, 560-573... 

While the term biotransformation generally implies inactivation and detoxification, there are exceptional cases where a metabolite is more chemically active or more toxic than the parent compound. In these situations, the processes of bioactivation and biotoxification are said to have occurred, respectively. An example of bioactivation is the formation of the commonly used drug acetaminophen from phenacetin in the liver (see Figure 3.2). The latter drug was once widely used as an analgesic agent but because of kidney toxicity has been replaced by other more potent, less toxic substitutes including, of course, acetaminophen itself. In this particular bioactivation pathway the process occurs via normal oxidative dealkylation. 

Fungi and bacteria metabolize a wide variety of PAHs (Cerniglia, 1993 Sutherland et al., 1995 Juhasz Naidu, 2000), although the principal pathways used by these groups are different. Some PAH bioactivation pathways found in mammals are also observed in microorganisms (Cerniglia Gibson, 1980). 

An example of this overall approach in elucidating novel bioactivation pathways is highlighted with studies on the potassium channel opener, maxipost (BMS-204352) (Figure 6.2), which undergoes a unique P450-mediated bioactivation reaction in rats, dogs, and humans to yield an electrophilic o-quinone-methide intermediate, which covalently binds to albumin in vivo in animals and human.33-34 Acidic hydrolysis of plasma collected after intravenous administration of [14C]-BMS-204352 to rats and human led to the characterization of a... 

To date, there are no examples where in silico tools have been utilized in a proactive fashion to predict reactive metabolite formation with small molecules. There are virtual or experimental techniques that can predict metabolic outcomes including the potential for forming reactive metabolites to some degree or the other. At best, these techniques have been used to rationalize published experimental observations on bioactivation pathways. Exploitation of these tools in drug discovery in a proactive fashion would necessitate additional experimental studies to validate the predictions. 

Troglitazone as Example for Multi-factorial Hepatotoxicity A prominent case of postmarketing withdrawal of a drug due to hepatotoxicity is the thia-zolidinedione insulin sensitizer drug troglitazone. Bioactivation pathways... 

FIGURE 10.11 Proposed bioactivation pathways of thiophene-containing model compound and the schemes for trapping reactive intermediates. 

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