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 investigated in Sprague-Dawley (SDs) compared with Fischer 344s (F344s) rats after administration of cyclophosphamide (CPA). Animals received a single dose of CPA with sacrifice occurring 6 days post-treatment. At 130 mg/kg, male F344s displayed a greater sensitivity to CPA, 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 correlated (r2 = 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 2C11 activity (P < .05) and thyroxine (P < .01), respectively, were observed, whereas activities characteristic of P450s 2C11, 3A2, 2A2, 2C6 and 2E1/1A2 were unaffected in SDs at this dose. CPA also produced suppression of P450 in female SDs, including female-specific 2C12. Correlation was observed between the loss of P450 expression and change in body weight after treatment in both male and female animals, suggesting that CPA downregulates P450 expression secondary to decreased caloric intake. The anorectic effect of CPA is believed to result from potent central nervous system stimulation, accompanied by a state of adaptive hypothyroidism. It has been reported that CPA produces "feminization" of P450 expression in male rats. However, our findings suggest the alternative explanation that the effects of CPA on P450 expression result from decreased caloric intake.
Kraner
J C
JC
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, USA.
Morgan
E T
ET
Poet
T S
TS
Born
S L
SL
Burnett
V L
VL
Halpert
J R
JR
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002384:Catalysis; D003520:Cyclophosphamide / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D012737:Sex Factors; D013045:Species Specificity; D013739:Testosterone / Q000097:blood; D013974:Thyroxine / Q000097:blood*; D014284:Triiodothyronine / Q000097:blood*
D007527:Isoenzymes; D014284:Triiodothyronine; D013739:Testosterone; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D013974:Thyroxine