Phenobarbital (PB)-mediated induction of five forms of cytochrome P450 (CYP2B1, CYP2B2, CYP3A1, CYP2A1, and CYP2C6) and epoxide hydrolase is highly suppressed, at the transcriptional level, in Wistar Furth (WF) relative to Fischer 344 (F344) female rats. Either hypophysectomy or thyroid hormone depletion by methimazole largely reverses the suppression in WF animals. Here we show that this strain-dependent polymorphism and unusual endocrine regulation extend to PB induction of phase II enzymes UGT2B1 uridine diphosphate-glucuronosyl transferase (UDPGT), PB-inducible aldehyde dehydrogenase (ALDH), and glutathione transferases Ya1 and Ya2 (GSTYa1 and GSTYa2). UDPGT, ALDH, GSTYa1, and GSTYa2 had mRNA levels induced by PB in a similar strain-dependent manner (F344 > WF). The extent to which mRNA induction was favored in female F344 relative to female WF was gene dependent (UDPGT 5 x; ALDH 15 x; GSTYa1 2 x; GSTYa2 3-5 x). Again, thyroid suppression by methimazole treatment selectively enhanced mRNA induced levels in female WF animals to remove much of the strain difference. Since thyroid hormone action is linked to fatty acid (FA) homeostasis, we tested the possibility that FAs participated in this endocrine polymorphism by using three isocaloric diets: low fat (LFD), polyunsaturated fatty acid (PUFAD), or saturated fatty acid (SFAD). The LFD suppressed PB-induction of CYP mRNA and protein in WF but not F344 rats. This had no parallel in phase II mRNA induction, possibly indicating that FA and thyroid hormone effects are uncoupled. We conclude that the PB-response mechanism for induction of multiple P450 and phase II genes share a pathway that has as a common feature the linkage between chemical stimulation and thyroid hormone suppression that is seen in female WF relative to female F344 rats but not in male rats.