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Transgenic Analysis of Human Drug–Metabolizing Enzymes: Preclinical Drug Development and Toxicology
Table 5.
Receptor and Transcription Factor Deletions
| Gene | Phenotype | Genetic Background | Comments | Citation |
|---|---|---|---|---|
| a 50% perinatal mortality, survivors apparently viable, fertile and normal. b Genetic background enriched to at least 75% C57BL/6 to increase postnatal survival of PPARδ null pups to Mendelian ratios. | ||||
| AhR | Hepatic fibrosis and impaired immune system | 129xC57BL/6 | Disruption of exon 1 leads to 50% mortality in perinatal period Resistant to TCDD toxicity Reduced retinoic acid metabolism | (42) |
| Viable, fertile but with hepatic defects | 129xC57BL/6 | Disruption of exon 2 | (43) | |
| Viable, fertile | 129xC57BL/6 | Disruption of exon 2; lacZ reporter Resistant to BaP carcinogenicity | (41) | |
| ARNT | Embryonic lethal | 129xC57BL/6 | Disruption of bHLH domain Defects in neural tube closure, embryo rotation | (46) |
| Embryonic lethal | Not stated | Disruption of bHLH domain Defective angiogenesis of yolk sac and branchial arches, stunted development | (45) | |
| Loss of induction via AhR in liver | 129xC57BL/6 | Disruption of exon 6 Conditional deletion (Mx-1-Cre) | (47) | |
| Nrf2 | None | 129xC57BL/6 | Disruption of exons 4,5; lacZ reporter Increased sensitivity to acetaminophen | (49) |
| Develop autoimmune nephritis >60 weeks old | 129xICR | Disruption of exon 5; lacZ reporter Increased sensitivity to acetaminophen | (50) | |
| AhR/Nrf2 | Nonea | 129xC57BL/6xICR | Response to 3MC and BHA abolished | (55) |
| PPARα | None | 129xC57BL/6 | Disruption of exon 8 Lack of response to peroxisome proliferators | (57) |
| PPARδ | Reduced growth; Smaller gonadal adipose stores; Reduced brain myelination; Increased epidermal hyperplastic response to TPA | 129xC57BL/6b | Disruption of last exon | (59) |
| PPARγ | Embryonic lethal | Not stated | Disruption of zinc finger coding region | (61) |
| Altered cholesterol homeostasis | 129xC57BL/6 | Conditional deletion (macrophages) | (62) | |
