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The Potential of Microbial Mediated Fermentation Products of Herbal Material in Anti-Aging Cosmetics
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Biotransformation may also constitute the conversion of an active metabolite to a more active metabolite, as in the instance of tectoridin to 6-hydroxygenistein and kakkalide to 6-hydroxybiochanin (Figure 2.3). This is referred to as bioactivation. Tsuchihashi et al. (2009) cultured Peptostreptococcus productus with tectoridin and kakkalide isoflavones from Pueraria flowers, which yielded 6-hydroxygenistein and 6-hydroxybiochanin A, respectively. While tectoridin and kakkalide did not show any hepatoprotective activity (EC50 > 200 µM), 6-hydroxygenistein and 6-hydroxybiochanin A showed significant activity, producing EC50 values of 18.3 µM and 14.5 µM, respectively (Tsuchihashi et al., 2009).
Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
For most xenobiotic chemicals, metabolism is not a one-step process, but occurs via multiple competing and sequential pathways. The formation of inactive, more water-soluble metabolites is the general endpoint of this process (detoxification), but in some cases activation to toxic metabolites can occur (bioactivation). Clearly the relative rates of these reactions may determine to a large extent the response of the organ to foreign chemical exposure. Any alterations in the relative activities of the bioactivation and detoxification pathways could influence the extent of toxicity of a chemical to the kidney.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
As stated previously, biotransformation functions as a mechanism for modifying xenobiotics such that they acquire increased polarity and hence become excretable. This process can occur by one or more of several competing pathways, all of which lead to products that are excretable but differing in the relative degrees of electrophilicity of the intermediates in the pathways. Whether bioactivation or detoxification occurs is influenced by the relative activities of the competing pathways for biotransformation. Table 4-2 (Guengerich and Liebler, 1985) lists xenobiotics for which the liver is a major target for toxicity and/or carcinogenicity and for which toxicity and carcinogenicity require biotransformation. Previous reviews by Gillette et al. (1974), Miller and Miller (1981b), Neal and Halpert (1982), Nelson (1982), Macdonald (1983), Ortiz de Montellano and Correia (1983), Guengerich and Liebler (1985), Dipple et al. (1985), and Kadlubar and Hammons (1987) provide detailed descriptions of biotransformation pathways and intermediates leading to toxicity and carcinogenicity for these compounds.
Metabolic activation of deferiprone mediated by CYP2A6
Published in Xenobiotica, 2021
Xiaojiao Zheng, Xu Wang, Zifang Ding, Wei Li, Ying Peng, Jiang Zheng
Recombinant human P450 enzyme incubation study showed that CYP2A6 played the major role in the metabolic activation of DFP (Figure 6). However, we cannot exclude the contribution of other P450 enzyme to the bioactivation, particularly multiple P450 enzymes are involved in the metabolic activation of DFP. Although some drugs are reportedly metabolized by human CYP2A6 but not necessarily by rat CYP2A1/2 (Messina et al. 1997; Miksys et al. 2000), rat CYP2A1/2 are known to share about 60% homology in amino acid sequence with human CYP2A6 (Martignoni et al. 2006). Our microsomal inhibition study showed that the presence of methoxsalen inhibited the formation of M3 in both human and rat microsomal incubations (Figure 7). Despite this, more work is in need to ensure rat CYP2A1/2 and human CYP2A6 share the similarity in catalysis of the metabolic activation of DFP.
Risk assessment of components in tobacco smoke and e-cigarette aerosols: a pragmatic choice of dose metrics
Published in Inhalation Toxicology, 2021
Peter M. J. Bos, Lya G. Soeteman-Hernández, Reinskje Talhout
For risk assessment of concentration-driven systemic effects (such as depression of the central nervous system (CNS)), emphasis may be more on the exposure concentration than on the exposure duration although both should be taken into account. For dose-related systemic effects, the absorbed dose can be considered as dose metric, depending on the exposure scenario that underlies the hazard information. However, it should be realized that the larger the differences in concentration and duration between the smoking scenario and the exposure regimen underlying the hazard information, the larger the uncertainties will be in the final assessment. It cannot be assessed beforehand whether this will result in an under- or overestimation of risks involved. For instance, a high dose rate may result in saturation of a biotransformation pathway and the impact on health risks will depend on whether this pathway includes bioactivation or deactivation (see for instance the example of benzene hereafter).
Moonlighting in drug metabolism
Published in Drug Metabolism Reviews, 2021
Approximately, 30 enzyme families catalyze drug and chemical metabolism and nearly 300 genes encode the enzymes of drug metabolism (Williams 1959; Jakoby and Ziegler 1990; Gibson and Skeet 2001; Uetrecht and Trager 2007; Kedderis 2018; Hu et al. 2019) (www.PharmaADME.org). These mechanistically diverse enzymes are characterized by broad substrate selectivities and a preference for lipid-soluble compounds and catalyze oxidation-reduction, conjugation, and hydrolytic reactions. Although there is apparently no agreement as to the teleological utility of drug metabolizing enzymes, most serve to convert potentially toxic chemicals into less pharmacologically active and less toxic metabolites that are more readily excretable. With some compounds, however, metabolites are formed that are more toxic than the parent compounds, a process termed ‘bioactivation’ (Anders 1985; Uetrecht 2003; Elfarra 2008).