SUPPRESSION OF RAT HEPATIC-MICROSOMAL CYTOCHROMES P450 BY CYCLOPHOSPHAMIDE IS CORRELATED WITH PLASMA THYROID-HORMONE LEVELS AND DISPLAYS DIFFERENTIAL STRAIN SENSITIVITY

Strain differences in cytochrome P450 (P450) expression were investiga ted in Sprague-Dawleys (SDs) compared with Fischer 344s (F344s) rats a fter administration of cyclophosphamide (CPA). Animals received a sing le dose of CPA with sacrifice occurring 6 days post-treatment. At 130 mg/kg, male f344s displayed a greater sensitivity to GPA, as evidenced by a 68% loss of total hepatic microsomal P450 compared with only 35% in SDs. The most dramatic change in P450 was the loss of 2C11 (84% in F344s, 52% in SDs). In the SD, individual rat 2C11 activity was corre lated (r(2) = 0.76), with the level of plasma thyroxine in that animal . In male F344s administered CPA at 50 mg/kg, 43 and 44% losses in 2C1 1 activity (P <.05) and thyroxine (P <.01), respectively, were observe d, whereas activities characteristic of P450s 2C11, 3A2, 2A2, 2C6 and 2E1/1A2 were unaffected in SDs at this dose. CPA also produced suppres sion of P450 in female SDs, including female-specific 2C12. Correlatio n was observed between the loss of P450 expression and change in body weight after treatment in both male and female animals, suggesting tha t CPA downregulates P450 expression secondary to decreased caloric int ake. The anorectic effect of CPA is believed to result from potent cen tral nervous system stimulation, accompanied by a state of adaptive hy pothyroidism. It has been reported that CPA produces ''feminization'' of P450 expression in male rats. However, our findings suggest the alt ernative explanation that the effects of CPA on P450 expression result from decreased caloric intake.