Mechanisms of chiral recognition in xenobiotic metabolism and drug‐receptor interactions

Abstract

KEY WORDS: substrate enantioselectivity, product enantioselectivity, MichaelisMenten analysis, intrinsic activity, potency, receptor affinity, efficacy CONCEPTUAL STEPS IN THE INTERACTION OF XENOBIOTICS WITH BIOLOGICAL SYSTEMSChiral recognition is an essential component of pharmacological events, be they of a pharmacokinetic (e.g., xenobiotic metabolism) or pharmacodynamic nature (e.g., receptor-mediated effects). Thus, an in depth understanding of pharmacological events cannot dispense with the molecular mechanisms underlying chiral recognition. But at which step(s) of pharmacological events does chiral recognition occur? This is the question addressed here. A number of scientists have found answers in their respective fields, yet a unifying view is given here that may expand our perception of the fundamental similitude between pharmacodynamic and pharmacokinetic events?From a general viewpoint, the interaction of a xenobiotic, and more generally of any chemical compound, with a biological system can be broken down into three steps' : 1. A penetration step (measured as partition), involving entry of the compound into the compartment (cell, organelle, or membrane) of the acceptor, receptor, or enzyme.2. A recognition step (measured as affinity), involving the binding (complex formation) to the acceptor, receptor, or enzymatic site.3. An activation step (measured by potency, velocity, etc.), involving the molecular effect itself, e.g., activation or blockade of receptor, enzymatic reaction leading to metabolite formation.These three steps are conceptual ones, and, as such, have the utility and limitation of schematic perceptions. Also, situations exist that involve only two of the three steps. Thus, penetration is bypassed when working with isolated enzymes or macromolecules. Binding does not occur in nonenzymatic reactions, and there is no activation in "silent" interactions with various macromolecules and membranes. Yet, in spite of its simplificative character, this model appears useful in interpreting pharmacodynamics as well as pharmacokinetics events.In this short review, it is demonstrated that in pharmacological processes the binding and/or the activation step can contribute to chiral recognition. Note that the penetration step, which involves comparatively weak interactions with chiral macromolecular assemblies, should also contribute to the chiral recognition of bioactive agents. Lack of explicit data, however, precludes a fair assessment of the (presumably weak) contribution of 0 1989 Alan R. Liss, Inc. the penetration step, and the discussion to follow will be restricted to the binding and activation steps. XENOBIOTIC METABOLISMEnantioselectivity in xenobiotic metabolism can take two quite distinct forms, namely, substrate enantioselectivity and product enantioselectivity. The former involves the differential metabolism of two enantiomeric substrates under identical conditions, and it must be contrasted with product enantioselectivity and, more generally, with product stereoselectivity, which implies t...

Quantification of urinary excretion of ethosuximide enantiomers and their major metabolites in the rat

“…route: 1.122 (day 1), 1.391 (day 2) and 1.748 (day 3). These data suggest substrate-product stereoselectivity for the metabolism of rac-ethosuximide [10]. Previous researchers had only obtained two peaks corresponding to 2-(1-hydroxyethyl)-2-methylsuccinimide (isomers 'A' and 'B') using achiral techniques [11,12].…”

Chiral Recognition in Biochemical Pharmacology: An Overview

“…In addition to substrate stereoselectivity, metabolic reactions also display product stereoselectivity, which is defined as (a) the differential formation (in quantitative and/or qualitative terms) of two or more stereoisomeric metabolites, (b) from a single substrate having a suitable prochiral center or face (JENNER and TESTA 1973;MAYER and TESTA 1994;TESTA 1986bTESTA , 1988TESTA , 1989TESTA , 1990TESTA , 1995JENNER 1976, 1980;TESTA and MAYER 1988). Examples of metabolic pathways producing new centers of chirality in substrate molecules are: ketone reduction, reduction of carbon-carbon double bonds, hydroxylation of prochiral methylenes, oxygenation of tertiary amines to N-oxides, and oxygenation of sulfides to sulfoxides.…”

“…From a general viewpoint, the interaction ofaxenobiotic, and more generally of any chemical compound, with a molecular machine (receptor, enzyme, transporter, etc.) can be broken down into two steps (TESTA 1989): Fig. 7.…”

Stereoselectivity in clinical pharmacokinetics and drug development

“…such that the prefixes of (+) and (-) are synonymous with (d) and (l) to denote optical rotation but not with (D) and (L) or (R) and (5), which provide descriptors of absolute configuration, Although guidelines have been laid down in IUPAC rules and monographs (12) and in the Cahn, Ingold and Prelog (13) convention suggesting that both the absolute descriptors, R or S, should be placed before the rotational optical descriptor in parenthesis (+) or (-), the instructions to contributors in the journal Chirality ask for the reverse whilst in the Chemical Abstract Rules (14) the optical descriptors are omitted. Further complications arise with isomerism at double bonds, diastereomers; with interchangeable Z or E or cis or trans descriptors, where there may not be a 50150 mixture, where both diastereomer and enantiomers co-exist in the same molecule, when a crystallised salt, e.g.…”

“…Although there is still not full agreement on the relative order of absolute and optical descriptors (12,15), there is general agreement that (t! ) and (l) should not be used so as to avoid confusion with the absolute descriptors of D and L given to carbohydrates and amino acids (12).…”