Alterations in the subcellular distribution of Guanylate cyclase and its responsiveness to nitric oxide in diethylstilbestrol-induced renal tumors.

The cyclic GMP content of diethylstilbestrol-induced renal tumors in the male golden hamster was increased nearly 130-fold over that in kidney from control animals. Cyclic GMP in tumors was 91.80 +/- 19.18 pmoles cyclic GMP/mg protein compared to 0.72 +/- 0.07 in control kidneys. Cyclic AMP in tumors was also increased over control, however, to a much lesser degree (2.7-fold). In control kidneys, 84.6% of homogenate guanylate cyclase activity was recovered in the 100,000 X g supernatant fraction. Total homogenate guanylate cyclase activity from diethylstilbestrol-induced renal tumors was increased 5.5-fold over that in control kidneys and only 8.1% was associated with the 100,000 X g supernatant fraction. Neither the soluble or particulate guanylate cyclase from renal tumors could be activated by nitric oxide. The unresponsiveness of tumor guanylate cyclase to nitric oxide was independent of the cation cofactor, and not due to a shift in the dose response curve for nitric oxide. Responsiveness to nitric oxide was not restored by thiols, sugars, other proteins, or hemoglobin. Basal cyclic AMP formation by soluble guanylate cyclase from renal tumors was dramatically increased over that observed in control kidneys, and could not be increased further by nitric oxide. This is the first study of cyclic GMP and guanylate cyclase in a primary estrogen-induced tumor. The possibility that the changes observed in guanylate cyclase from diethylstilbestrol-induced renal tumors are related to in vivo activation of the enzyme by epoxide metabolites of diethylstilbestrol is discussed.