High RA exposure activates enzymes causing:
Retinoic acid levels tightly regulated by synthesis via retinaldehyde dehydrogenases and degradation via cytochrome P450 family Cyp26 enzymes. Exogenous high RA dose activates retinoic acid response elements in Cyp26A1 promoter, strongly inducing RA catabolic enzymes aimed at restoring homeostasis. Enhanced enzyme activity persists beyond clearance of exogenous RA, accelerating endogenous RA turnover leading to precipitous drop below normal required for ongoing organogenesis. This induced catabolism creates long-lasting RA deficiency phase more teratogenic than initial excess, explaining paradox where similar phenotypes arise from both RA surplus and deficiency due to disrupted morphogen balance during critical windows.
Ref: Gilbert, Developmental Biology, 12th ed., Chapter 20: High RA induces enzymes causing RA deficiency.