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Metabolism of 2-Methoxyestrone in Normal Men^*

Departments of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical School (C.L., C.F.) Worcester, Massachusetts 01605
Worcester Foundation for Experimental Biology (A.F., K.I.H. W.) Shrewsbury, Massachusetts 01545

Address requests for reprints to: Dr. Christopher Longcope, Department of Obstetrics and Gynecology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01605.

We studied, in four normal men, the metabolism of 2-methoxyestrone (2-MeOE₁) using pulse injections of either [³H]2MeOE₁ (two men) or [¹⁴C]methoxy-2-MeOE₁ plus [³H]2-MeOE₁ (two men) by analysis of blood samples drawn at increasing time intervals after the pulse and of urine collected for 5 days. The disappearance from the blood of radioactivity as 2-MeOE₁ could be characterized as a function that was the sum of three exponentials. The mean ± SE value for the initial volume of distribution was 32 ± 9 liters, and the mean MCR was 2470 ± 770 liters/day. The disappearance of total ³H radioactivity from the blood was considerably slower, with a mean MCR of 290 ± 30 liters/day, indicating the presence of a slowly turning over pool of 2-MeOE₁ metabolites, probably including the 2-MeOE₁ 3-sulfate conjugate. The disappearance of total ¹⁴C radioactivity was slower than that of total ³H, indicating considerable demethylation of 2-MeOE₁ with a very slow excretion of ¹⁴C from the released methyl group.

In none of the subjects could we find in the blood radioactivity as unconjugated [³H]2-hydroxyestrone ([³H]2-OHE₁). However, examination of the urine indicated that considerable demethylation of [³H]2-MeOE₁ had occurred. At least 64% of the urinary ³H-containing metabolites from the mixed dose had lost the ¹⁴C-bearing methoxylcarbon atom. The fractionated metabolites were qualitatively and quantitatively similar to those found earlier for [³H]2-OHE₁.

We conclude that 2-MeOE₁, which of itself has little biological activity, can act as a pool of potentially active 2-OHE₁ in the tissues.

^* This work was supported by NIAMDD Grant AM-20915.

Received September 23, 1982.