Although many fields of endeavour emerge owing to the coalescence of the work and observations of numerous individuals, there is usually one seminal event that unites and acts as a catalyst to stimulate and advance the process. Such was the case with Alexander Ure. Up to this point it had been speculated that chemicals taken into the body may undergo bio-transformation, akin to the digestion of nutrients, but no unequivocal and quantitative experiments had been performed before those of Ure. Following his observations the subject began to flourish; to him may be attributed the beginnings of xenobiochemistry and the field now known as drug metabolism.

Although there had been many previous inklings, the field of xenobiotic metabolism (as we know it today) began with an experiment reported in the 1841 literature proclaiming that the ingestion of benzoic acid led to the subsequent excretion of hippuric acid in human urine. A metabolic transformation undertaken by a living organism. One worker involved in the early stages of this discovery was Wilhelm Keller, although very little information about him is readily available. Hopefully, this article will go some way to counter this dearth and also highlight Keller's pioneering contribution in the development of the fields of drug metabolism and xenobiochemistry.

Agrochemicals include herbicides, insecticides, and fungicides and improve both the quality and quantity of agricultural produce. Residues of pesticides in foodstuffs are common and are analyzed by national or supra-national organizations in rolling programs; the results are then published. The main modes of action for pesticides are via dysregulation of either neuronal pathways or energy supply. Because these metabolic routes are often shared to some extent with mammals, pesticides may also affect human populations when their residues are ingested. Possible areas of concern include potential for endocrine disruption, the "cocktail effect" where multiple residues are present in a product at the same time, and alterations to the gastrointestinal microbiome. In particular, chronic exposure to cleaning agents and disinfectants may disrupt the bacterial profile in the gut. The long-term effects, if any, of pesticides on human health might be elucidated using "omics" techniques with human cell lines.

Sulfur is unusual in that it is a mineral that may be taken into the body in both inorganic and organic combinations. It has been available within the environment throughout the development of lifeforms and as such has become integrated into virtually every aspect of biochemical function. It is essential for the nature and maintenance of structure, assists in communication within the organism, is vital as a catalytic assistant in intermediary metabolism and the mechanism of energy flow as well as being involved in internal defense against potentially damaging reactive species and invading foreign chemicals. Recent studies have suggested extended roles for sulfur-containing molecules within living systems. As such, questions have been raised as to whether or not humans are receiving sufficient sulfur within their diet. Sulfur appears to have been the "poor relation" with regards to mineral nutrition. This may be because of difficulties encountered over its multifarious functions, the many chemical guises in which it may be ingested and its complex biochemical interconversions once taken into the body. No established daily requirements have been determined, unlike many minerals, although suggestions have been proposed. Owing to its widespread distribution within dietary components its intake has almost been taken for granted. In the majority of individuals partaking of a balanced diet the supply is deemed adequate, but those opting for specialized or restrictive diets may experience occasional and low-level shortages. In these instances, the careful use of sulfur supplements may be of benefit.

S-Carboxymethyl-l-cysteine is a mucolytic agent used as adjunctive therapy in the treatment of respiratory disorders. Various mechanisms of action have been proposed but few studies have attempted to link the required in vitro concentrations with those achieved actually in vivo during clinical therapy. The data from several published studies has been re-analysed by WinNonlin using non-compartmental analysis modelling, Phoenix modelling and Classic PK compartmental modelling for both single (500-1500 mg) and multiple oral administration of the drug. Multiple dose modelling indicated maximum peak concentrations (C-max) ranging from 1.29 to 11.22 mu g/ml and those at steady state (C-ss(av)) from 1.30 to 8.40 mu g/ml. For the standard therapeutic regimen of 3 x 750 mg (2250 mg/day) these values were 1.29-5.22 mu g/ml (C-max) and 1.30-3.50 mu g/ml (C-ss(av)). No accumulation was observed. Hence, only the pharmacodynamic studies reporting significant effects below c.10 mu g/ml were likely to occur in vivo and these were mainly gene-related mechanisms. The majority of events, although demonstrable in vitro, required levels much greater than possible to achieve in the clinical situation. Such unappreciated disregard for in vitro-in vivo 'concentration matching' may lead to erroneous conclusions regarding mechanisms of action for many drugs as well as for S-carboxymethyl-l-cysteine.

Mice that were heterozygous dominant for the enu1 and enu2 mutation in phenylalanine monooxygenase/phenylalanine hydroxylase (PAH) resulted in hepatic PAH assays for S-carboxymethyl-L-cysteine (SCMC) that had significantly increased calculated Km (wild type (wt)/enu1, 1.84-2.12 fold increase and wt/enu2 a 2.75 fold increase in PAH assays). The heterozygous dominant phenotypes showed a significantly reduced catalytic turnover of SCMC (wt/enu1, 6.11 fold decrease and wt/enu2 an 11.25 fold decrease in calculated Vmax). Finally, these phenotypes also had a significantly reduced clearance, CLE (wt/enu1, 13.02 fold and wt/enu2, a 30.80-30.94 fold decrease) The homozygous recessive phenotype (enu1/enu1) was also found to have significantly increased calculated Km (2.16 fold increase), a significantly reduced calculated Vmax (11.35-12.33 fold decrease) and CLE (24.75-25.00 fold decrease). The enu2/enu2, homozygous recessive phenotype had no detectable PAH activity using SCMC as substrate. The identity of the enzyme responsible for the C-oxidation of L-phenylalanine (L-Phe) and the S-oxidation of SCMC in wt/wt (BTBR) mice was identified using monoclonal antibody and selective chemical inhibitors and was found to be PAH. This in vitro mouse hepatic cytosolic fraction metabolism investigation provides further evidence to support the hypothesis that an individual possessing one variant allele for PAH will result in a poor metaboliser phenotype that is unable to produce significant amounts of S-oxide metabolites of SCMC.

Over the years, numerous studies have supported the premise that individuals possessing the "slow acetylator" phenotype are more at risk from developing drug side-effects. Most prominent amongst these reports are those concerned with hepatotoxicity and peripheral neuropathy following treatment with isoniazid, lupus-like symptoms during procainamide therapy and experiencing hypersensitivity reactions to the various sulphonamide derivatives. Similarly, "slow acetylators" undergoing heavy exposure to arylamines and related carcinogens are more likely to develop bladder cancer. Contrariwise, there appears a slight risk of "rapid acetylators" developing pancreatic tumours.Other therapeutic agents for which polymorphic N-acetylation plays a minor role in their metabolism have been investigated but any impact of this metabolic difference on clinical efficacy or associated toxicity is still under question. In the search for clues as to the underlying aetiology, patient groups with many disease states have been examined for association with differences in N-acetylation and the majority have provided data that could be interpreted as equivocal. Studies have given contradictory, often opposing, results, calculated risk factors that are (perhaps) just significant but certainly not high, and patients within the cohorts who are always exceptions. Undoubtedly, other as yet unappreciated factors are at play.

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

Abstract Background The S-oxidation of S-carboxymethyl-L-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis. In the present investigation, the original observations have been extended and confirmed. Methods Meta-analysis of previously published investigations into the S-oxidation polymorphism together with new subject data was evaluated. Results The incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) was found to be 3%–7% within healthy and non-neurological disease populations, whereas 38% of the Parkinson’s disease subjects and 39% of the amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson’s disease was calculated to be 33.8 [95% confidence interval (CI), 13.3–86.1] and for amyotrophic lateral sclerosis was 35.2 (95% CI, 13.0–85.1). Conclusions The possible involvement of the enzyme responsible for this S-oxidation biotransformation reaction, phenylalanine hydroxylase, should be further investigated to elucidate its potential role in the mechanism(s) of toxicity in susceptible individuals displaying these diseases. The “Janus hypothesis,” possibly explaining why phenylalanine hydroxylase is a biomarker of neurodegenerative disease susceptibility, together with the general theme that this concept may apply to many other hitherto unsuspected enzyme systems, is presented.

1. Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-l-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age. 2. Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-l-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders; although, underlying mechanisms were unknown. 3. Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.

The events leading up to the discovery of genetically controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field. The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a success or failure within the present clinical arena.

ObjectivesTo determine the K-m, V-max, cofactor, activator and inhibitor requirements of human cysteine dioxygenase and S-carboxymethyl-l-cysteine S-oxygenase with respect to both l-Cysteine and S-carboxymethyl-l-cysteine as substrates. MethodsIn vitro human hepatic cytosolic fraction enzyme assays were optimised for cysteine dioxygenase activity using l-Cysteine as substrate and the effect of various cofactors, activators and inhibitors on the S-oxidations of both l-Cysteine and S-carboxymethyl-l-cysteine were investigated. Key findingsThe results of the invitro reaction phenotyping investigation found that although both cysteine dioxygenase and S-carboxymethyl-l-cysteine S-oxygenase required Fe2+ for catalytic activity both enzymes showed considerable divergence in cofactor, activator and inhibitor specificities. Cysteine dioxygenase has no cofactor but uses NAD(+) and NADH(H+) as pharmacological chaperones and is not inhibited by S-carboxymethyl-l-cysteine. S-carboxymethyl-l-cysteine S-oxygenase requires tetrahydrobiopterin as a cofactor, is not activated by NAD(+) and NADH(H+) but is activated by l-Cysteine. Additionally, the sulfydryl alkylating agent, N-ethylmaleimide, activated carboxymethyl-l-cysteine S-oxygenase but inhibited cysteine dioxygenase. ConclusionsHuman hepatic cytosolic fraction cysteine dioxygenase activity is not responsible for the S-oxidation of the substituted cysteine, S-carboxymethyl-l-cysteine.

•A narrative review is presented of the potential toxicity of plastic particles to humans.•Nanoparticles are more readily absorbed than microparticles.•Atmospheric pollution and ingestion of shellfish are major sources of plastic particles.•Toxicity is unlikely unless absorption of plastic particles is high and continuous.

Unravelling the molecular basis of thalidomide embryotoxicity, which is remarkably species-specific, is challenging in view of its low toxicity in the mature animal. Employing data derived solely from proven sensitive primate species or susceptible strains of rabbit, the structure-activity relationship of over 50 compounds which are, arguably, congeners of thalidomide has been reviewed. The molecular requirement for 'thalidomide-type' teratogenicity was highly structure dependent. Both the phthalimide and glutarimide groups were essential for embryopathic activity, although minor substitutions in either or both rings could be tolerated without a loss of toxicity. An α-linkage between the two cyclic structures was essential; a β-link resulted in a complete loss of embryopathic activity. Crucially, this α-configuration provided a centre of asymmetry enabling the existence of stereoisomers. The thalidomide molecule is not a static entity and under physiological conditions it undergoes a number of intra- and inter-molecular reactions. Besides irreversible hydrolysis, its keto-enol tautomerism, base-assisted proton transfer and glutarimide ring rotation lead to rapid interconversion of the thalidomide enantiomers. These enantiomers form equilibria between themselves and also between both homochiral and heterochiral dimers. It is proposed that the more energetically favourable and stable heterochiral dimer of thalidomide is an active agent that possesses the structural features of the paired nucleotides of the double-stranded DNA. Its capacity to enter into hydrogen bonding interactions affects DNA expression in a chaotic manner without causing permanent mutations. This disruption may well be concentrated at nucleotide sites known to be involved in specific promoter regions of the genome.

Although it is believed widely that the various routes of xenobiotic metabolism are now all known and effectively understood, occasionally there emerges a metabolite that signals a novel biotransformation pathway, especially where the xenobiotic may in some way interact with the myriad processes of intermediary metabolism. There are a few reports in the literature where saturated short-chain dicarboxylic acids have been exploited as conjugating agents and these unusual xenobiotic metabolites subsequently excreted intact in the urine.Initially suggested by unpublished observations bolstered by extensive experience of the authors and colleagues in the field of xenobiochemistry, this narrative review has been supplemented by a search of bibliographic databases and the subsequent scrutiny of numerous peer-reviewed research articles. The resultant sparse and widely dispersed information has been examined, analysed and presented in this review.Xenobiotic conjugation with dicarboxylic acids has been demonstrated to occur within several domains of life; microorganisms, plants, invertebrates and mammals. However, considering the number of xenobiotic metabolism investigations that have been undertaken reports of such conjugations are exceedingly rare.Dicarboxylic acid condensation with xenobiotic molecules may occur at nitrogen centres, or more precisely with a primary or secondary amine, that is at nitrogen still possessing a replaceable hydrogen atom. Both aliphatic amines and arylamines may be substrates with many of the free amino groups being formed by previous Ndealkylation reactions. Hopefully, awareness of this metabolic route will be raised and researchers will be enthused to search for this type of conjugate.