Humanized mouse models cytochrome

Ohtsuki, S., Kawakami, H., Inoue, T., Nakamura, K., Tateno, C., Katsukura, Y, Obuchi, W, Uchida, Y, Kamiie, J., Horie, T., and Terasaki, T. (2014). Validation of uPA/SCID mouse with humanized liver as a human liver model protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases by LC-MS/MS. Drug Metab Dispos 42, 1039-1043. 

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

Bogaards, J. J., Bertrand, M., Jackson, R, Oudshoom, M. J., Weaver, R. J., van Bladeren, P. J., and Walther, B. (2000). Determining the best animal model for human cytochrome P450 activities a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 30, 1131-1152. 

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