Transgenic Analysis of Human Drug–Metabolizing Enzymes: Preclinical Drug Development and Toxicology

Table 2.

Potential Problems with Transgenic Mouse Lines in Pharmacokinetics and Toxicology

Problem	Solution
Genetic background modifies phenotype	• Backcross to defined genetic background, with matched wild-type controls
	• Generate multiple independent lines
High background “noise” due to overlapping substrate specificities between, or structural homology within, gene families	• Delete endogenous interfering genes (may be technically difficult if several spread throughout the genome)
Species differences in gene regulation	• Express transgene under endogenous promoter
Integration position affects genotype	• Generate multiple independent lines
Gene deletion is embryonic lethal or causes significant welfare problems	• Use conditional deletion (i.e., Cre/LoxP)
Residual activity remains after gene targeting (i.e., truncated protein acts as dominant negative)	• Delete gene completely