Bioactivation mechanism

P. S. Magee, D. R. Henry, and. H. Block, Probing Bioactive Mechanisms, ACS Symposium Series No. 413, American Chemical Society, Washington, D.C., 1989. 

Bolton, J. L. Acay, N. M. Vukomanovic, V. Evidence that 4-ally 1-o-quinones spontaneously rearrange to their more electrophilic quinone methides potential bioactivation mechanism for the hepatocarcinogen safrole. Chem. Res. Toxicol. 1994, 7, 443 450. 

The selective renal carcinogenicity of dichloroacetylene may be due to a bioactivation mechanism that involves glutathione S-conju-gate formation, translocation to the kidneys, and subsequent renal metabolism to yield reactive electrophiles presumably responsible for carcinogenicity. ... 

The QSAR data show that glucuronidation can be either a detoxification or bioactivation mechanism, depending chemical structure. For N SAIDs, it appears to be mostly a detoxification mechanism. Nonetheless, the toxicity of acyl glucuronide and glucoside adducts (espedally as it relates to isomerization and protein adduct formation) must be considered when designing carboxylic acids [38]... 

One type of isosteric substitution that should have tremendous potential in the design of safer commercial chemicals is replacement of hydrogen with fluorine. Since many bioactivation mechanisms of chemicals involve cytochrome P450-mediated hydrogen atom abstraction to yield toxic metabolites, it would seem plausible that replacement of such a hydrogen atom with fluorine would provide a safer isosteric analog, without affecting commercial efficacy. 

Glennon RA, Seggel MR. Interaction of phenylisopropylamines with 5-HT2 receptors a QSAR analysis. In Magee PS, ed., Probing Bioactive Mechanisms. Washinton DC ACS Press, 1989 264-280. 

Eder E, Schiffmann D, Dornbusch K, et al. 1986. Direct and indirect genotoxicity of alkylating allylic compounds competing bioactivation mechanisms. In 4th International Congress Toxicology,... 

Bioactive Mechanism of Interaction Between Anthocyanins and Macromolecules Like DNAand Proteins... 

To achieve a site-specific drug delivery through a target-specific bioactivation mechanism. 

Several mechanisms have been identified for the generation of nephrotoxicants following conjugation of halogenated hydrocarbons with glutathione (Table 6). These mechanisms include intramolecular cyclization, activation by cysteine conjugate S-lyase, and facilitated renal accumulation of the toxicant. Examples of each of these bioactivation mechanisms will be discussed in the following sections. 

There is complete reduction of a p- or o-quinone to the corresponding hydroquinone or catechol, respectively. In the human liver, carbonyl reductase may play a role in the reduction of some quinones. Catechols are primary substrates for catechol o-me-thyl transferase, but also undergo sulfation. However, for the antitumor quinones, mitomycin C, adriamycin, and daunomycin, two-electron reduction serves as an efficient bioactivation mechanism, elegantly affirming the concept of bioreductive alkylation for the preferential bioactivation of antitumor prodrugs with oxygen deficient tumors. 

Venhuis et al. observed a particularly original oxidative bioactivation mechanism by which an a, 3-unsaturated cyclic ketone is converted to the corresponding catechol and delivered enantioselectively into the CNS (Figure 36.29b). This concept can be generalized and has the potential to lead to new anti-Parkinson treatments. " ... 

Certain bioactivation mechanisms involve several chemical seqnences, some of them being oxidative, others being rednctive. 

Table 32.1 Some major toxophoric groups and their bioactivation mechanisms...

B Reductive bioactivation of omeprazole Mixed Bioactivation Mechanisms... 

Staub, R- E., Sparks. S. E, Quistad. G. B., and Casida, J. E. (1995). 5-methylation as a bioactivation mechanism for mono-and dithiticarbamate pesticides as aldehyde dehydrogenase inhibitors. Chem. Res. Toxicol 8, 1063-1069. 

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