Bioactivation and detoxication

Cashman JR, Xiong YN, Xu L, et al. N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3) role in bioactivation and detoxication. J Pharmacol Exp Ther 1999 288(3) 1251—1260. 

Hlavica P. N-oxidative transformation of free and N-substituted amine functions by cytochrome P450 as means of bioactivation and detoxication. Drag Metab Rev. 2002 34 451H-77. 

Guengerich, F. P. Bioactivation and detoxication of toxic and carcinogenic chemicals. Drug Metabol. Disp. 21 1-6, 1993. 

Figure 1. Bioactivation and detoxication of methyl parathion. AH is arylester hydrolase, CH is carboxylester hydrolase, G is glutathione transferase, and M is monooxygenase.

Jewell H, Maggs JL, Harrison AC et al (1995) Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25 199-217 follow DJ, Mitchell JR, Zampaglione N et al (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11 151-169... 

Williams DE, Reed RL, Kedziersk B, Dannan GA, Guengerich FP, Buhler DR (1989) Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver. Drug Metab Dispos 17 387-392... 

Figure 6-12 Bioactivation and competing detoxication pathways of the selective estrogen receptor modulator raloxifene.

The conclusion of the study was that interindividual variations in the amount of human cytochrome 2A6 and 2E1 could contribute to the susceptibility of environmental procarcinogens including those derived from tobacco smoke. Cytochromes P-450 largely bioactivate nicotine and nicotine-related nitrosoamines to electrophilic materials. Presumably, the balance between bioactivating enzyme activity and detoxicating enzyme activity is important in determining the overall susceptibilities of humans to exposure to chemicals. Below, the properties of several additional enzymes in nicotine detoxication are described. 

Stiborova M, Levova K, Barta F, Shi Z, Frei E, Schmeiser HH, Nebert DW, Phillips DH, Arlt VM (2012) Bioactivation versus detoxication ofthe urothelial carcinogen aristolochic acid I by human cytochrome P450 lAl and 1A2. Toxicol Sci 125 345-358... 

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. 

Results of the above-outlined research into physico-chemical and medico-biological properties of BAS, conducted at the Institute of Surface Chemistry of the NAS of Ukraine in collaboration with Vinnitsa State Medical University, named after N.I. Pirogov, and other medical institutions of Ukraine and Russia give reasons to infer that Silics is an active medicinal substance which on its own can function as a therapeutic agent. Sorptive detoxication with the aid of the bioactive silica brings about a profound effect in the case of acute intestinal infections, diarrheas of various origins, viral hepatitis, as well as for local treatment for pyoinflammatory diseases and purulent wounds. 

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. 

Typically, metabolic processes leading to detoxication of the parent compound are favored and activation pathways are minor however, some conditions cause a shift toward bioactivation events becoming predominant. When an organism is exposed to a large quantity of a xenobiotic, it may saturate or activate certain enzymes, thereby altering the resultant detoxication pathway. A number of physiological and genetic factors, as well as metabolic and chemical interactions, may also favor the activation of a parent compound as opposed to its detoxication. 

Metabolic interactions resulting from concurrent detoxication of xenobiotics may modulate the activity of enzymes and thereby result in bioactivation reactions or a decrease in efficacy of a drug. The previous example of induction of CYP2E1 by ethanol and subsequent activation of acetaminophen to NAPQI is a case of metabolic interaction as well, where the mechanism is enzyme induction. 

Currently there is a significant amount of information about the way biocatalysts from animals detoxicate and bioactivate drugs of abuse. 

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). 

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