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

Carcinogenesis Studies Branch, National Cancer Institute, Bethesda, Maryland

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.

¹ Presented in part at the 56th Annual Meeting of the American Association for Cancer Research, April 7–10, 1965, in Philadelphia. This article is dedicated with gratitude, respect and admiration to Dr. Jacob Furth on the occasion of his 70th birthday. The present study on endocrine effects in liver carcinogenesis could not have been undertaken without the Furth functional pituitary tumor.

³ The abbreviations used are: FAA, N-2-fluorenylacetamide (also 2-acetylaminofluorene); N-OH-FAA, N-hydroxy-N-2-fluorenylacetamide (also N-hydroxy-2-acetylaminofluorene; N-2-fluorenylacetohydroxamic acid); 3-OH-FAA, the 3-hydroxy derivative, etc.; FA, 2-fluorenamine (also 2-aminofluorene); and Tris, tris(hydroxymethyl)aminomethane.

² Visiting Scientist, NIH, on leave of absence from the Institute of Physical and Chemical Research, Tokyo, Japan.

Received 7/21/65.