Xenobiotics metabolic bioactivation

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

Intestinal microflora are capable of impacting xenobiotic metabolism by causing enterohepatic circulation and delayed excretion and by catalyzing many of the reactions that also occur as a result of detoxication and bioactivation reactions by phase I and II enzymes. The carbohydrate amygdalin, which contains a cyanide substituent, is found in the kernels of various fruits including plum, cherry, peach, and apricot as well as in almonds. Hydrolysis by the [f-glucosidases in intestinal bacteria yields reactive intermediates capable of releasing cyanide. 

Xenobiotics can be absorbed across the cellular barriers and may be biologically active and possibly toxic to the cell. Metabolism of these molecules by enzymes to hydrophilic metabolites is a prerequisite for their eventual elimination from the body. However, in some cases bioactivation may also occur, and such metabolites may be toxic. Xenobiotic metabolism has therefore been widely studied since the early 1800s [1]. The parent molecule and the products of metabolic pathways may also be involved in drug interactions where they... 

Figure 43-1 I Schematic view of the role of NAT enzymes in the metabolism of aromatic amines. N-acetylation might be a detoxification reaction in a number of cases however, after N-hydroxylation of aromatic amines (e.g., by CYP enzymes), NAT enzymes can bioactivate these intermediates by either 0-acetylation or intramolecular N,0-acety transfer, leading to the formation of nitrenium ions, which might react with DNA or alternatively be detoxified by, for example, GST enzymes. Importantly, it is shown that a number of other biotransformation enzymes are also involved in the metabolism of aromatic amines as well. (Redrawn from Wormhoudt LW, Commandeur jNM, Vermeuien NPE. Genetic polymorphisms of human N-acetyitransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999 29 59-124. Reproduced by permission from Taylor and Francis, Inc.)...

One is probably Richard Tecwyn Williams who introduced the Phase I and II classification of xenobiotics metabolism reactions. Although his emblematic book was called Detoxication mechanisms, he estimated that, in some cases, metabolism may increase toxicity. He also considered that this bioactivation may occur during the Phase II reactions (usually considered as detoxication reactions), and not only that of Phase I (functionalization reactions). 

Mechanisms of liver injury have been divided into two categories intrinsic and idiosyncratic. Intrinsic injury may lead to steatosis, necrosis, cholestasis, or a mixed form of damage, often with minimal inflammation (Sturgill and Lambert, 1997). Intrinsic liver injury is a predictable, reproducible, dose-dependent reaction to a toxicant (Dahm and Jones, 1996 Sturgill and Lambert, 1997 Zimmerman, 1999 Pineiro-Carrero and Pineiro, 2004). A threshold dose exists for xenobiotics causing intrinsic liver injury. There is commonly a predictable latent period between the time of exposure and clinical evidence of liver injury. This type of liver injury accounts for the vast majority of toxic liver injury and is often caused by reactive products of xenobiotic metabolism, most commonly electrophiles and free radicals. A few drugs cause intrinsic liver injury without bioactivation. An abbreviated summary of mechanisms of intrinsic liver injury is illustrated in Figure 42.1. 

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

Mulder GJ. Drug metabolism inactivation and bioactivation of xenobiotics. In Mulder GJ, Dencker L, eds. Pharmaceutical Toxicology. London, UK Pharmaceutical Press, 2006. 

Although flavonoids can modulate UGT, SULT, and COMT activity toward other xenobiotics, their impact after chronic consumption on their own metabolism has not been examined, even though such activity could substantially alter their bioactivity.105-107 This relationship may become even more complex in older subjects due to the inverse association between age and the adaptability of phase II metabolism.42-108... 

Zhu, B.T., Catechol-O-Methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics Importance in pathophysiology and pathogenesis, Curr Drug Metab., 3, 321, 2002. 

Bioactivation Metabolism of a xenobiotic to a chemically more reactive metabolite. 

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