The Biochemistry of Drug Metabolism – An Introduction

Abstract

This review continues a general presentation of the metabolism of drugs and other xenobiotics started in a recent issue of Chemistry & Biodiversity. This Part 2 presents the numerous oxidoreductases involved, their nomenclature, relevant biochemical properties, catalytic mechanisms, and the very diverse reactions they catalyze. Many medicinally, environmentally, and toxicologically relevant examples are presented and discussed. Cytochromes P450 occupy a majority of the pages of Part 2, but a large number of relevant oxidoreductases are also considered, e.g., flavin-containing monooxygenases, amine oxidases, molybdenum hydroxylases, peroxidases, and the innumerable dehydrogenases/reductases.

Characterisation of the Metabolites of 1,8-Cineole Transferred into Human Milk: Concentrations and Ratio of Enantiomers

“…2,3-Dehydro-1,8-cineole itself might be generated by dehydrogenation of 1,8-cineole or dehydration of α2-hydroxy-, β2-hydroxy- or α3-hydroxy-1,8-cineole [48]. The 2- and 3-hydroxy-cineoles could be further oxidised to the respective oxo-cineoles [49] and a back-reaction might also be conceivable. Generally, many human enzymes are capable of catalysing the reaction of a carbonyl- to a hydroxyl-function (e.g.…”

“…Generally, many human enzymes are capable of catalysing the reaction of a carbonyl- to a hydroxyl-function (e.g. aldo-keto-reductases, carbonyl-reductases) [49,50], but focussed studies with molecules comparable to oxo-1,8-cineoles have, as of yet, not been accomplished. However, some bacterial enzymes have been reported to be responsible for very similar reactions such as the reduction of camphor to borneol [51], and human carbonyl reductases have such a broad substrate specificity [52] that it is well conceivable that such a back-reaction of oxo- to hydroxy- 1,8-cineole might take place, as also proposed by Ishida et al for thujone and carvone [53].…”

In-source formation of N-acetyl-p-benzoquinone imine (NAPQI), the putatively toxic acetaminophen (paracetamol) metabolite, after derivatization with pentafluorobenzyl bromide and GC–ECNICI-MS analysis

“…It is likely that this process involves loss of the sole H atom of the acetamide group as a hydride to form uncharged NAPQI (i.e., CH 3 CO-N C 6 H 4 O) (see (R6)), the intermediate toxic metabolite of acetaminophen formed by CYP-catalyzed oxidation of acetaminophen [1][2][3][4][5][6][7]. The lower the ion-source temperature was, the more NAPQI was formed.…”

“…1). Oxidation of acetaminophen by various isoforms of the phase I enzyme system cytochrome P450 (CYP) leads to formation of the highly reactive N-(4-oxo-2,5-cyclohexadien-1-ylidene)acetamide which is better known as N-acetyl-p-benzoquinone imine, NAPQI (O C 6 H 4 N-COCH 3 , MW 149) [3] (Fig. 1).…”

Acetaminophen Prodrug: Microwave-Assisted Synthesis andin vitroMetabolism Evaluation by Mass Spectrometry

“…This toxic metabolite is highly reactive and responsible for hepatic injury. 15 Although widely used, in the literature there is a restricted number of publications dealing with the synthesis of propacetamol. [16][17][18][19][20][21][22] In pioneering work, Cognacq 19 prepared propacetamol hydrochloride through the reaction of diethylamine with 4-acetamidophenyl-2-chloroacetate.…”