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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Lidocaine also undergoes hydrolytic conversion to result in 2,6-dimethylaniline (2,6-xylidine) (Figure 3.56) (Abdel-Rehim et al. 2000; Parker et al. 1996), a potential human carcinogen (Koujitani et al. 1999). Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzes lidocaine and monoethylglycinexylidide, but not glycinexylidide, to 2,6-xylidine (Alexson et al. 2002). 2,6-Dimethylaniline (2,6-Xylidine) can be further oxidized by CYP2A6 and 2E1 to 4-amino-3,5-dimethylphenol (i.e., 4-hydroxyxylidine) (Gan et al. 2001), but oxidation of the amino group to metabolites such as N-(2,6-dimethylphenyl) hydroxylamine is also noted in human and rats. 2,6-Xylidine can also be hydroxylated at the 3- or 4-position of the aromatic ring. In addition, 2,6-xylidine can be carboxylated to 2-amino-3-methylbenzoic acid in rabbits (Kammerer and Schmitz 1986). 4-Hydroxy-2,6-xylidine in glucuronide form is the major urinary metabolite found in man, accounting for 72.6% of an administered dose of lidocaine (Keenaghan and Boyes 1972; Tam et al. 1987). This metabolite is also the major metabolite in dogs (35.2%) but lesser in the urine of rats (12.4%) and guinea pigs (16.4%) (Keenaghan and Boyes 1972). Monoethylglycinexylidide is present in the urine in free and glucuronide- and sulfate-conjugated forms, while glycinexylidide is present mostly in the free form (Tam et al. 1990). Only 3% of lidocaine is excreted as unchanged drug. Phase II conjugation of N-(2,6-dimethylphenyl)hydroxylamine may result in reactive esters that decompose to a reactive nitrenium ion capable of reacting with protein and DNA. Reaction of the nitrenium ion with water is a second pathway for the formation of 4-amino-3,5-dimethylphenol (Gan et al. 2001). Further oxidation of 4-amino-3,5-dimethylphenol leads to the formation of the toxic iminoquinone species. Lidocaine can also be hydroxylated to 4-hydroxylidocaine to a minor extent in rats (Coutts et al. 1987) and rabbits (Kammerer and Schmitz 1986) and undergoes N-oxidation to its N-oxide seen in vitro only (Patterson et al. 1986).
Metabolic Activation of Aromatic Amines and Amides and Interactions with Nucleic Acids
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
Similarly, the occurrence of acetyl esters of N-hydroxy amides in vivo has not been described. The mechanism of substitution by carcinogenic N-acetoxy-arylamides was studied in detail by Scribner et al.117 and by Scribner and Naimy.49,110 In the presence of nucleophiles less basic than acetate ion, the 2-fluorenyl and 4-stilbenyl N-acetoxy amides showed unimolecular ionization, whereas the corresponding 4-biphenyl and 3-phenanthryl derivatives appeared to form acetate ions by bimolecular displacement. In the presence of the more basic citrate trianion, all four esters showed increased rates of decomposition, and these approached maximal levels with increasing concentrations of the nucleophile. These observations were explained by the authors by postulating the formation of an intermediate ion pair in which the unshared pair of electrons of the nitrogen of the nitrenium ion is in a nonbinding sp2-orbital and the nitrogen p-orbital is vacant. The extent to which this ion pair reacts further or returns to the ground state would be determined by the stabilization provided by the aromatic system. The relative differences in chemical properties were further interpreted by Scribner and Naimy110 on the basis of Hückel molecular orbital calculations for the nitrenium ion. As opposed to the biphenyl derivative, a triplet state was postulated for the fluorenyl acetylnitrenium ion as illustrated in Figure 9. Experimental support for the triplet state was obtained from the reactivity of various N-acetoxy-arylacetamides towards the stable free radical 2,2-diphenyl-1-picrylhydrazyl. The fluorenyl derivative is much more reactive than the phenanthryl derivative, whereas the biphenyl and stilbenyl compounds did not react at all with this free radical. However, the rate of loss of the N-acetoxy group did not always correspond to the extent of substitution by methionine or guanosine. Similarly, the rates of decomposition of the N-acetoxy-arylamides did not correspond with the carcinogenic activities of these compounds or of their parent N-hydroxy derivatives. This lack of correlation is not unexpected in view of other important factors which are operative in vivo, such as penetration of the carcinogen into the target cell and the different rates of activation and deactivation occurring within the target cells.
Metabolism of the antipsychotic drug olanzapine by CYP3A43
Published in Xenobiotica, 2022
Jie Zhao, David Machalz, Sijie Liu, Clemens Alexander Wolf, Gerhard Wolber, Maria Kristina Parr, Matthias Bureik
The fission yeast strains that coexpress human cytochrome P450 reductase (CPR) and either CYP1A2, CYP2D6, CYP3A4, CYP3A5, CYP3A7, or CYP3A43.1, respectively, have been described previously (Drăgan et al. 2011; Neunzig et al. 2011; 2012; Durairaj et al. 2019), while the three strains expressing the CYP3A43 mutants were cloned in this investigation. All strains used in this study are listed in Table 1. The sites of olanzapine metabolism were predicted by SMARTCyp (Rydberg et al. 2010), a web-based software that predicts CYP-mediated metabolic liability of heavy substrate atoms (Supplementary Table 2). Metabolites M1 (2′-hydroxymethyl olanzapine) and M2 (N-desmethyl olanzapine) showed the highest probability of matching with a predicted SoO, followed by M3 (olanzapine nitrenium ion), M4 (3′-hydroxymethyl olanzapine) and M5 (2-hydroxymethyl olanzapine). Three of these olanzapine metabolites (M2, M3 and M5) have been reported before (Soderberg and Dahl 2013; Geib et al. 2020). Thus, all of these metabolites were included in our analysis. Moreover, we also looked for M6 (2-formyl olanzapine) and M7 (2-carboxy olanzapine) as they result from further biotransformation of M5 and, moreover, M7 is well known (Soderberg and Dahl 2013). The chemical structures of all metabolites are shown in Figure 1.
A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism
Published in Drug Metabolism Reviews, 2019
Jingxuan Chen, Sibo Jiang, Jin Wang, Jwala Renukuntla, Suman Sirimulla, Jianjun Chen
4-Aminobiphenyl, a trace component of cigarette smoke and hair dyes, manifests its toxic effects after bioactivation (Wang et al. 2015a, 2015b). The traditional model of aminobiphenyl carcinogenesis has shown that the chemical is oxidized, esterified, and then spontaneously hydrolyzed, producing a highly reactive nitrenium ion (Chen et al. 2005). The metabolite further contributes to the DNA-adducts formation and thus initiates liver tumor growth in mice. Both CYP2E1 and CYP1A2 are responsible for N-hydroxylation of aminobiphenyl, the first step in the bioactivation of aminobiphenyl (Wang et al. 2015a, 2015b). Interestingly, postnatal exposure of mice to aminobiphenyl causes a higher incidence of liver tumors in males than in females. However, no correlation was found between sex or CYP1A2 function and the corresponding damage of DNA; yet sex-differences in CYP2E1-dependent oxidative stress and antioxidant response to the substrate contribute to the observed sex difference in tumor incidence (Wang et al. 2015b).