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The Effect of Adrenalectomy, Hypophysectomy, and Castration on the Urinary Metabolites of 2-Acetylaminofluorene in the Rat^*

Prabhakar D. Lotlikar, Makoto Enomoto, Elizabeth C. Miller and James A. Miller

( McArdle Memorial Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin)

Adrenalectomized or hypophysectomized young male rats excreted in the urine only about 40 per cent as much N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) after intraperitoneal injection of a test dose of AAF as unoperated rats; similar results were obtained with adrenalectomized rats given 2-diacetylaminofluorene. The excretion of N-hydroxy-AAF by adrenalectomized rats given either AAF or 2-diacetylaminofluorene was restored to about 90 and 75 per cent, respectively, of normal by treatment with cortisone and deoxycorticosterone. Administration of adrenocorticotropic hormone for 10 days largely restored the excretion of N-hydroxy-AAF by hypophysectomized rats given injections of AAF. In adrenalectomized-hypophysectomized young rats, the excretion of N-hydroxy-AAF after injection of AAF was reduced to 30 per cent of normal. Administration of cortisone and deoxycorticosterone acetate restored the excretion to 75 per cent of normal; growth hormone had little effect. Thyroidectomy of young rats and replacement therapy with either iodide or thyroid powder had minimal effects on the excretion of metabolites of AAF.

Adrenalectomized-hypophysectomized-castrated adult male rats excreted only 40 per cent as much N-hydroxy-AAF as normal rats given injections of AAF. Administration of cortisone and deoxycorticosterone with or without testosterone increased the excretion of N-hydroxy-AAF by the triply operated rats to 3–4 times the control level, but did not alter the excretion by unoperated rats. Castration alone or in combination with adrenalectomy caused a 2-3-fold increase in the excretion of N-hydroxy-AAF; this increase was entirely prevented by testosterone and was partially prevented by cortisone administration.

The above endocrine ablations and replacement therapies had much less influence on the excretion of ring-hydroxy derivatives after administration of AAF. Adrenalectomy did not alter the excretion of N-hydroxy-AAF after the administration of this compound, nor the ability of liver homogenates to reduce N-hydroxy-AAF to AAF.

It is suggested that one of the roles of adrenal hormones in promoting hepatic carcinogenesis by AAF and 2-diacetylaminofluorene in the rat, as shown by other investigators, may be to promote the formation or maintenance of higher levels of the N-hydroxy derivative.

^* This investigation was supported by Grants CA-07175 and CRTY-5002 of the National Cancer Institute, United States Public Health Service; by a grant from the Jane Coffin Childs Memorial Fund for Medical Research; and by the Alexander and Margaret Stewart Trust Fund. We wish to thank Mrs. Diane McKechnie for excellent technical assistance. A preliminary report of some of these data has been made (20).

Present address: Department of Pathology, University of Tokyo.

Received 6/29/64.