Metabolic activation pathways

Figure 5. Metabolic activation pathways of BA. MFO abbreviates for the cytochrome P-450-containing mixed-function oxidases. The absolute configurations of the metabolites are as shown.

Accordingly, the contribution of this metabolic activation pathway to the formation of covalently-bound adducts of arylamides with cellular proteins and nucleic acids has been the subject of numerous investigations, and has been reviewed extensively by Mulder (25). From these and more recent data (4,26,27) it is apparent, particularly in the case of N-hydroxy-AAF Tn-OH-AAF), that in vivo formation of reactive N-sulfonyloxy derivatives is primarily... 

Although several N-methyl-substituted arylamines have been shown to be carcinogenic (184-186), metabolic activation pathways have been investigated primarily for the hepatocarcinogenic aminoazo dyes, N-methyl-4-aminoazobenzene (MAB) and its 3 -methyl derivative (9,21, 22,187,188). N-Hydroxy-N-methyl arylamines are generally regarded as proximate carcinogenic metabolites (22,187,189) and have been shown to be converted to electrophilic N-sulfonyloxy derivatives by hepatic sulfotransferases (9,187) or to reactive N-arylnitrones by air oxidation (21). 

Most of the over 400 N-nitroso compounds that have been tested for carcinogenic activity have been found to be carcinogenic [13, 39]. It is well known that the predominant initial metabolic activation pathway for N-nitrosamines is a-hydroxyl-... 

Substitution at the a-carbon with acidic group(s), fluoro group(s), or bulky group (s) has been shown to diminish or abolish their carcinogenicity. This is because the initial metabolic activation pathway for N-nitrosamines is a-hydroxylation. 

Fig. 10.2 Metabolic activation pathways leading to mutation in nitro-aromatic compounds. Ring-oxidation might occur in the ortho, meta, or para position. Shown in the figure is the para metabolic ring-oxidation. Figure adapted from [15]...

Is the positive result a consequence of an in vitro specific metabolic activation pathway/in vitro specific active metabolite ... 

Figure 32.8. Metabolic activation pathway for cyclophosphamide. Acrolein, phosphoramide mustard, and nornitrogen mustard are the immunotoxic metabolites.

Melikian, A.A. American Health Foundation Quantification of urinary metabolites metabolic activation pathways Health Effects Institute... 

Nesnow, S., Easley, J., Curti, S., Ross, J., Nelson, G., Sangaiah, R., and Gold, A. (1991). Morphological transformation and DNA adduct formation by benz[/]aceanthrylene and its metabolites in C3H10T1/2CL8 cells Evidence for both cyclopenta-ring and bay-region metabolic activation pathways. Cancer Res S, 6163-6169. 

Teitel, C.H., Snawder, J.E., Von Tungeln, L.S., and Kadlubar, F.F. (1997) Immunochemical, 32P-postlabeling, and GC/MS detection of 4-aminobiphenyl-DNA adducts in human peripheral lung in relation to metabolic activation pathways involving pulmonary N-oxidation, conjugation, and peroxidation. Mutat. Res., 378, 97-112. 

Furman PA, Murakami E, Niu C, Lam AM, Espiritu C, Bansal S, Bao H, Tolstykh T, Steuer HM, Keiiman M et ai (2011) Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661. Antiviral Res 91 120-132... 

The metabolism of trichloroethylene has been the subject of several reviews (3, 38, 196, 217, 255, 471). Trichloroethylene was shown to be metabolically activated via epoxidation of its olefinic bond. The formation of trichloroethylene oxide in the presence of liver microsomes was determined by spectral studies of the cytochrome P-450 complex (465, 466). The identification of chloral as an in vitro metabolite (61, 403) and of trichloromethanol and trichloroacetic acid as in vivo metabolites in rats (94) and dogs (60) supports the metabolic activation pathway outlined in Fig. 20. 

Figure 2. Metabolic activation pathways for nitropolycyclic aromatic hydrocarbons.

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