Prediction of drug sensitivity in individuals with atypical serum cholinesterase based on in vitro biochemical studies.

V,,,, and K,,, values with twenty-five “atypical” and thirty-seven “usual” cholinesterase human sera were determined for the cholinesterase substrates procaine, tetracaine, benzoylcholine, o-nitrophenylbutyrate, cu-naphthylacetate and aspirin. Aspirin was demonstrated to be a substrate for serum cholinesterase. For each of these substrates the ratio of V,,substrate to V,,,, benzoylcholine was found to be similar with atypical and usual cholinesterase sera. Therefore, we concluded that the respective turnover numbers for atypical and usual cholinesterase were the same. Both atypical and usual cholinesterase sera had turnover numbers of 255 min-’ for procaine, 74 min-i for tetracaine, 7200 min-’ for aspirin in the presence of 50 mM CaClr, 36,000 min-’ for cu-naphthylacetate, and 48,000 mini for o-nitrophenylbutyrate, at 25” in 0.1 M Tris-Cl buffer, pH 7.4. A comparison of K,,, values for atypical and usual cholinesterase indicated that the positively charged substrates, as well as aspirin in the presence of CaClr, showed a lower affinity with atypical than with usual cholinesterase, while neutral esters had nearly the same K, for atypical and usual cholinesterase. These results imply that individuals with atypical cholinesterase will hydrolyze therapeutic doses of positively charged substrates and aspirin at reduced rates, but neutral substrates should be hydrolyzed at normal rates. The clinical importance of serum cholinesterase (EC 3.1.1.8; acylcholine acyl-hydrolase; also known as pseudocholinesterase and butyrylcholinesterase) was first recognized when certain patients developed respiratory paralysis for several hours after receiving normal doses of succinylcholine. These patients hydrolyzed the drug very slowly because they had inherited an “atypical” cholinesterase, which has a much lower affinity for succinylcholine, than does “usual” cholinesterase [ 1, 21. Based upon this pharmacogenetic explanation for succinylcholine sensitivity, one might predict that individuals with atypical cholinesterase would also show considerable reduction in the rates of hydrolysis of other drugs known to be substrates for the enzyme. For example, Kalow [3] as well as Foldes et al. [4] have suggested that atypical cholinesterase patients might be more susceptible to certain local anesthetics. In the present report the possibility of increased drug sensitivity of individuals with atypical cholinesterase was investigated by means of in vitro biochemical studies.. Sera from patients with atypical * Supported by a Horace H. Rackham predoctoral fellowship to R. J. V.; bv U.S. Public Health Service Grants NS 15871 and GM -27028; and by a grant from the HoffmanwLa Roche Foundation. t Present address: Pharmacology Department, University of North Carolina Medical School, Chapel Hill, NC 27514, U.S.A. $ Address correspondence to: Oksana Lockridge, Pharmacology Department, Medical Science I, Room M6323, University of Michigan, Ann Arbor, MI 48109, U.S.A. cholinesterase, as well as from normal individuals, were characterized with respect to their affinities (K,,, values) and maximum velocities of enzymatic hydrolysis (V,,,, values) with various ester substrates. The compounds selected for study are known to be substrates of cholinesterase in human serum, and no other esterase in human serum contributes significantly to their hydrolysis [5-81. The substrates were classified according to their net charge at pH 7.4, and it was found that neutral compounds were distinguished as a group from all other substrates, in that only neutral compounds had the same K,,, value for both atypical and usual cholinesterases.