A Comparison of 2‐Hydroxyestradiol and U‐0521 (3′4′‐Dihydroxy‐2‐methylpropiophenone, Upjohn) as In Situ and In Vitro Inhibitors of Tyro sine Hydroxylase

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Abstract
Feedback inhibition of tyrosine hydroxylase by catechols was evaluated using in situ and in vitro enzymes assays. The 3 catechol compounds used were norepinephrine, 2-hydroxyestradiol and 3''4''-dihydroxy-2-H-methylpropiophenone (U-0521), U representing endogenous catecholamines, catechol estrogens and a synthetic catechol, respectively. The in situ experiments were performed with dissociated retinal cells from rats and with stationary phase adrenergic-like neuroblastoma cells (N1E-115). The catechol estrogen, 2-hydroxyestradiol, resembled the endogenous catecholamines in its potency to inhibit in vitro and in situ tyrosine hydroxylations with IC50 [concentration producing 50% inhibition] values of 10 .mu.M in vitro and 100 .mu.M in situ. The drug U-0521, used as an inhibitor of catechol-O-methyltransferase (COMT), was an inhibitor of tyrosine hydroxylase. It was more potent than the natural catechols, both in vitro and in situ, with IC50 values of 30-600 nM.