Effects of Pituitary Hormones and Prefeeding N-Hydroxy-N-2-fluorenylacetamide on the Metabolism of This Carcinogen and on Physiologic Parameters¹

The mechanism underlying the rapid hepatoma induction by the joint administration of the carcinogen N-hydroxy-N-2-fluorenylacetamide (N-OH-FAA)³ and pituitary hormones from a transplantable pituitary tumor, MtT/F4 (T), was investigated. For 8 weeks male Fischer rats were placed on (a) control Diet A, (b) N-OH-FAA, Diet K, (c) A diet + MtT, and (d) K diet + MtT, and were then injected with a single dose of N-OH-FAA-¹⁴C for in vivo studies, or the livers were incubated with labeled carcinogen in vitro.

Body weight gains were lower on Diet K and Diet A + T and lowest on K + T. Food and water intake and urine output were higher in groups on A + T, and especially so in those on K + T, which reflected sharply altered physiologic balances. Furthermore, the rectal temperatures of rats on A + T throughout and on K + T from Week 2–5 were appreciably higher than those of the respective controls, which suggested a higher metabolic rate induced by the pituitary hormones, and possibly implicated in the faster development of neoplasms. Groups A + T and K + T had hyperglycemia and glucosuria, which were particularly notable in rats on K + T. Group A + T, but not K + T, had marked proteinuria.

Radioactivity and glucosiduronic acids in 24-hr urine from labeled N-OH-FAA were highest in Group K + T, lowest in Group A, and intermediate in the other 2. The glucuronide of N-OH-FAA followed this pattern, which indicated decreased dehydroxylation and deacetylation caused by carcinogen and/or hormone pretreatment. In vitro studies with liver homogenates from the 4 experimental groups entirely confirmed these relative enzyme activities. Thus, rats implanted with MtT maintain lower amounts of detoxified products in the form of ring-hydroxylated metabolites and higher levels of N-OH-FAA, an additional factor possibly aiding hepatoma induction.