93 results found
Mitchell SC, Waring RH, 2022, Alexander Ure MD, FRCS (1808-1866), and the beginning of drug metabolism studies, JOURNAL OF MEDICAL BIOGRAPHY, ISSN: 0967-7720
Steventon GB, Mitchell SC, 2022, Phenylalanine monooxygenase and the 'sulfoxidation polymorphism'; the salient points., Drug Metab Pers Ther
Steventon GB, Mitchell SC, 2021, S-Carboxymethyl-l-cysteine: a multiple dosing study using pharmacokinetic modelling, XENOBIOTICA, Vol: 51, Pages: 865-870, ISSN: 0049-8254
Mitchell SC, 2021, Nutrition and sulfur., Adv Food Nutr Res, Vol: 96, Pages: 123-174, ISSN: 1043-4526
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.
Mitchell SC, 2020, N-acetyltransferase: the practical consequences of polymorphic activity in man., Xenobiotica, Vol: 50, Pages: 77-91
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.
Mitchell S, Steventon G, 2019, PREFACE for the special issue of xenobiotica on "pharmacogenetics of drug metabolism", XENOBIOTICA, Vol: 50, Pages: 1-2, ISSN: 0049-8254
Smith RL, Mitchell SC, 2019, Pharmacogenetics and drug metabolism: historical perspective and appraisal, XENOBIOTICA, Vol: 50, Pages: 3-8, ISSN: 0049-8254
Mitchell SC, Steventon GB, 2019, Phenylalanine 4-monooxygenase: the "sulfoxidation polymorphism", XENOBIOTICA, Vol: 50, Pages: 51-63, ISSN: 0049-8254
Steventon GB, Mitchell SC, 2019, The S-oxidation of S-carboxymethyl-L-cysteine in hepatic cytosolic fractions from BTBR and phenylketonuria enu1 and enu2 mice, XENOBIOTICA, Vol: 49, Pages: 495-502, ISSN: 0049-8254
Rawlings L, Turton L, Mitchell SC, et al., 2019, Drug S-oxidation and phenylalanine hydroxylase: a biomarker for neurodegenerative susceptibility in Parkinson's disease and amyotrophic lateral sclerosis., Drug Metab Pers Ther, Vol: 34
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.
Steventon GB, Mitchell SC, 2018, Phenylalanine hydroxylase: A biomarker of disease susceptibility in Parkinson's disease and amyotrophic lateral sclerosis (vol 118, pg 29, 2018), MEDICAL HYPOTHESES, Vol: 121, Pages: 88-88, ISSN: 0306-9877
Smith RL, Mitchell SC, 2018, Thalidomide-type teratogenicity: structure-activity relationships for congeners, TOXICOLOGY RESEARCH, Vol: 7, Pages: 1036-1047, ISSN: 2045-452X
Steventon GB, Mitchell SC, 2018, Phenylalanine hydroxylase: A biomarker of disease susceptibility in Parkinson's disease and Amyotrophic lateral sclerosis, MEDICAL HYPOTHESES, Vol: 118, Pages: 29-33, ISSN: 0306-9877
Steventon GB, Khan S, Mitchell SC, 2018, Comparison of the sulfur-oxygenation of cysteine and S-carboxymethyl-l-cysteine in human hepatic cytosol and the role of cysteine dioxygenase, JOURNAL OF PHARMACY AND PHARMACOLOGY, Vol: 70, Pages: 1069-1077, ISSN: 0022-3573
Mitchell SC, Steventon GB, 2018, Xenobiotic Conjugation with Dicarboxylic Acids, CURRENT DRUG METABOLISM, Vol: 19, Pages: 1130-1137, ISSN: 1389-2002
Mitchell SC, 2018, Xenobiotic C-sulfonate derivatives; metabolites or metabonates?, XENOBIOTICA, Vol: 48, Pages: 211-218, ISSN: 0049-8254
Waring RH, Harris RM, Mitchell SC, 2017, Drug metabolism in the elderly: A multifactorial problem?, MATURITAS, Vol: 100, Pages: 27-32, ISSN: 0378-5122
Mitchell SC, Waring RH, 2017, Fate of thianthrene in biological systems, XENOBIOTICA, Vol: 47, Pages: 731-740, ISSN: 0049-8254
Dumas ME, Domange C, Calderari S, et al., 2016, Topological Analysis of Metabolic Networks Integrating Co-Segregating Transcriptomes and Metabolomes in Type 2 Diabetic Rat Congenic Series, Genome Medicine, Vol: 8, ISSN: 1756-994X
Background: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus is caused by complex organ-specific cellular mechanisms contributing to impaired insulin secretion and insulin resistance. Methods: We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualise shortest paths between metabolites and genes significantly associated with each genomic block.Results: Despite strong genomic similarities (95-99%) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific metabotypes (mQTL) and genome-wide expression traits (eQTL). Variation in key metabolites like glucose, succinate, lactate or 3-hydroxybutyrate, and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing shortest path length drove prioritization of biological validations by gene silencing. Conclusions: These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulations and to characterize novel f
Mitchell SC, Smith RL, 2016, Trimethylamine-The Extracorporeal Envoy, CHEMICAL SENSES, Vol: 41, Pages: 275-279, ISSN: 0379-864X
Mitchell SC, Smith RL, 2016, Trimethylamine-The Extracorporeal Envoy., Chem Senses, Vol: 41, Pages: 275-279
One of the most widespread and efficient mechanisms that has evolved to enable communication between discrete and spatially separate living organisms is the use of specific chemical messengers. The organoleptic properties of certain molecules, even at concentrations that do not necessarily evoke a conscious response, have been exploited to transmit information across relatively large distances. The trimethylated derivative of ammonia is one such molecule that is ideally suited to this function and several species are known to respond to its presence. This review uniquely collects together and integrates widely dispersed data to show that trimethylamine also may serve a communicatory role in man, with its influence extending outside of the body.
Mitchell SC, Waring RH, 2016, Sulphate absorption across biological membranes, XENOBIOTICA, Vol: 46, Pages: 184-191, ISSN: 0049-8254
Mitchell SC, 2015, Xenobiotic conjugation with phosphate - a metabolic rarity, Xenobiotica, Vol: 46, Pages: 743-756, ISSN: 1366-5928
1. Although not unknown, the conjugation of a xenobiotic with phosphate appears a rarity amongst the routes available for foreign compound metabolism. This is especially true in mammals and may be somewhat surprising as conjugation with sulphate, a seemingly similar moiety, is commonplace.2. Information from the literature, where xenobiotic phosphate conjugates have been described or suggested, has been collated and presented in this article. By bringing together this diverse material, hopefully interest will be generated in this unusual xenobiotic reaction, and perhaps further research undertaken to better understand and delineate the reasons for its relative absence from the xenobiotic scene.
Vandenbossche E, Lucas C, Mistry L, et al., 2015, Phenylalanine monooxygenase and the sulfur oxygenation of S-carboxymethyl-L-cysteine in mice, Xenobiotica, Vol: 46, Pages: 379-384, ISSN: 1366-5928
1. The extent of sulfoxidation of the drug, S-carboxymethyl-l-cysteine, has been shown to vary between individuals, with this phenomenon being mooted as a biomarker for certain disease states and susceptibilities. Studies in vitro have indicated that the enzyme responsible for this reaction was phenylalanine monooxygenase but to date no in vivo evidence exists to support this assumption. Using the mouse models of mild hyperphenylalaninamia (enu1 PAH variant) and classical phenylketonuria (enu2 PAH variant), the sulfur oxygenation of S-carboxymethyl-l-cysteine has been investigated.2. Compared to the wild type (wt/wt) mice, both the heterozygous dominant (wt/enu1 and wt/enu2) mice and the homozygous recessive (enu1/enu1 and enu2/enu2) mice were shown to have significantly increased Cmax, AUC(0–180 min) and AUC(0–∞ min) values (15 - to 20-fold higher). These results were primarily attributable to the significantly reduced clearance of S-carboxymethyl-l-cysteine (13 - to 22-fold lower).3. Only the wild type mice produced measurable quantities of the parent S-oxide metabolites. Those mice possessing one or more allelic variant showed no evidence of blood SCMC (R/S) S-oxides. These observations support the proposition that differences in phenylalanine hydroxylase activity underlie the variation in S-carboxymethyl-l-cysteine sulfoxidation and that no other enzyme is able to undertake this reaction.
Panagopoulos P, Mitchell SC, Steventon GB, 2015, S-carboxymethyl-L-cysteine and it (R/S)-S-oxides in beagle dog plasma and hepatic cytosol, XENOBIOTICA, Vol: 45, Pages: 1047-1053, ISSN: 0049-8254
Mitchell S, Waring R, 2015, In memoriam Sybil Pauline James (9 February 1917--25 October 2014)., Xenobiotica, Vol: 45, Pages: 1-2
Mitchell SC, 2014, Xenobiotic-urea conjugates; chemical or biological?, XENOBIOTICA, Vol: 44, Pages: 1055-1066, ISSN: 0049-8254
Mitchell SC, Waring RH, Wilson ID, 2014, Ethyl sulphate, a chemically reactive human metabolite of ethanol?, XENOBIOTICA, Vol: 44, Pages: 957-960, ISSN: 0049-8254
Mitchell SC, Waring RH, Smith RL, 2014, Curiosities in drug metabolism, XENOBIOTICA, Vol: 44, Pages: 666-676, ISSN: 0049-8254
Mitchell S, Steventon G, Waring R, 2014, Drug peptide conjugates in human urine?, XENOBIOTICA, Vol: 44, Pages: 89-93, ISSN: 0049-8254
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