Alexander Ure MD, FRCS (1808-1866), and the beginning of drug metabolism studies.

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.

Snap-valve cerebral shunt design for intracranial pressure operation and ultrasound visualization.

Cerebral spinal fluid (CSF) shunts are the main treatment for hydrocephalus. They divert excess CSF from the ventricular system to the abdominal, pleural, or intravascular space where it is absorbed. The shunt valve regulates flow based on intracranial pressure (ICP) to maintain a physiologically stable and safe ICP. Shunt malfunction is difficult to detect, life-threatening and common. The present study demonstrates that snap-though buckling (STB) shells can be transformed into pressure-relief valves that act in the normal physiological range of ICP. Three different shell designs in this preliminary experiment were found to have opening and closing pressures that fall within the physiologically normal range of ICP of 6 to 25 cm H2O. Furthermore, these STB shells demonstrate a valve actuation that is visible by ultrasound and have an implantable form-factor that is similar to currently available shunt valves. The unique characteristics of STB shell valves have potential clinical applications for shunt monitoring using ultrasound imaging and can be fabricated from antibiotic-impregnated materials to mitigate shunt infection. These characteristics make STB valves attractive for future use in cerebral shunt systems.

Thalidomide-type teratogenicity: structure-activity relationships for congeners.

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 ß-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.

Plastic contamination of the food chain: A threat to human health?

Macro-plastic pollution is found in terrestrial and marine environments and is degraded to micro-particles (MP) and nano-particles (NP) of plastic. These can enter the human food chain either by inhalation or by ingestion, particularly of shellfish and crustaceans. Absorption across the gastrointestinal tract is relatively low, especially for MPs, which appear to have little toxicity. However, NPs are more readily absorbed and may accumulate in the brain, liver and other tissues in aquatic species and other animals. Studies using nanoparticles of other materials suggest that toxicity could potentially affect the central nervous system and the reproductive system, although this would be unlikely unless exposure levels were very high and absorption was increased by physiological factors.

Drug metabolism in the elderly: A multifactorial problem?

Whether or not an individual's drug metabolising capacity declines with advancing age is a vexing question. There is no clear evidence that drug metabolism itself ('the biologically-assisted chemical alteration of the administered parent molecule') is less efficient in healthy old age than at younger ages, whereas a decreased capacity may be associated with ill-health and frailty. However, elderly individuals do show a reduced enzyme induction capability and are less able to tolerate overdoses. It appears that the majority of deleterious clinical outcomes related to drug therapy in an elderly (usually ill or frail) population may be ascribed to various anatomical and physiological age-related changes. These may affect both pharmacodynamics and pharmacokinetics, but not necessarily drug metabolism. Information gleaned from animal studies undertaken mainly in rodents does not seem to be of relevance to humans and studies in healthy aged human populations may not highlight possible problems. However, certain circumstances may influence metabolic competence, and phenotyping rather than genotyping is of more value in identifying those susceptible to adverse drug reactions. This short review discusses the potential contributions of four factors (inflammation, circadian rhythm, gut microbes, epigenetic aspects) which may lead to alterations in drug metabolism with increasing age.

Metal powder absorptivity: modeling and experiment.

We present results of numerical modeling and direct calorimetric measurements of the powder absorptivity for a number of metals. The modeling results generally correlate well with experiment. We show that the powder absorptivity is determined, to a great extent, by the absorptivity of a flat surface at normal incidence. Our results allow the prediction of the powder absorptivity from normal flat-surface absorptivity measurements.

In utero exposure to carcinogens: Epigenetics, developmental disruption and consequences in later life.

The uterine environment is often viewed as a relatively safe haven, being guarded by the placenta which acts as a filter, permitting required materials to enter and unwanted products to be removed. However, this defensive barrier is sometimes breached by potential chemical hazards to which the mother may be subjected. Many of these toxins have immediate and recognisable deleterious effects on the embryo, foetus or neonate, but a few are insidious and leave a legacy of health issues that may emerge in later life. Several substances, falling into the categories of metals and metalloids, endocrine disruptors, solvents and other industrial chemicals, have been implicated in the development of long-term health problems in the offspring following maternal and subsequent in utero exposure. The mechanisms involved are complex but often involve epigenetic changes which disrupt normal cell processes leading to the development of cancers and also dysregulation of biochemical pathways.

Xenobiotic sulphation and its variability during inflammation: a factor in adverse drug reactions?

The interactions between disease processes and the metabolism of therapeutic drugs have not been systematically investigated. Inflammation, with the presence of pro-inflammatory cytokines, affects Phase 1 metabolism, particularly the activity of the CYP isoforms. Inflammatory factors also alter the activity of some Phase 2 enzymes, particularly the sulphotransferases (SULT isoforms) responsible for drug sulphonation and the enzyme pathway involved in the supply of sulphate for this reaction. Being ill may, therefore, in itself make drug metabolism unpredictable.

Post-translational activation of human phenylalanine 4-monooxygenase from an endobiotic to a xenobiotic enzyme by reactive oxygen and reactive nitrogen species.

An investigation into the post-translational activation of cDNA-expressed human phenylalanine 4-monooxygenase and human hepatic cytosolic fraction phenylalanine 4-monooxygenase activity with respect to both endobiotic metabolism and xenobiotic metabolism revealed that the reactive oxygen species (hydrogen peroxide and hydroxyl radical) and reactive nitrogen species (nitric oxide and peroxynitrite) could elicit the post-translational activation of the enzyme with respect to both of these biotransformation reactions. In virtually all instances, the K(m) values were decreased and the V(max) values were increased; the only exceptions observed being with hydrogen peroxide and L-phenylalanine. These effects were shown to occur at activator concentrations known to exist in physiological situations and, hence, suggest that reactive oxygen and reactive nitrogen species may cause, and may be involved with, the post-translational activation of phenylalanine 4-monooxygenase within the human body. This mechanism, in response to free-radical bursts, may enable the enzyme to expand its substrate range and to process certain xenobiotics as and when required.

Repetitive extragenic palindromic PCR for study of Streptococcus mutans diversity and transmission in human populations.

Pulsed-field gel electrophoresis (PFGE) is considered the "gold standard" for molecular epidemiological study. Repetitive extragenic palindromic PCR (rep-PCR) is less time-consuming and more suitable for analyzing large numbers of bacterial strains in human populations. PFGE and rep-PCR provide comparable genotyping results for investigating Streptococcus mutans diversity and transmission.

The menstrual cycle and drug metabolism.

Within the field of drug metabolism, when addressing quantitative aspects, an average value is traditionally quoted, commonly the arithmetic mean with perhaps an indication of spread. Better still a range of values may be given, thereby acknowledging that various factors may precipitate differences between individuals. A single subject, however, usually only merits a single value. Nevertheless, events such as an acute illness or concurrent drug therapy serve to alert that this value may change substantially over a relatively short time-period, although any potential effects of naturally occurring phenomena, such as the female menstrual cycle, are often overlooked or disregarded. Are the biochemical and physiological changes that occur during the menstrual cycle able to influence xenobiotic metabolism? Is the idea of a stable and unwavering baseline within a single healthy individual flawed? Is it time to reassess our thinking with regards to such aspects? This brief review explores these issues and examines information available within the literature for evidence of potential influences of menstrual cycle events upon drug metabolism, defined as the actual chemical alteration of the parent molecule into another chemical species.

Foreign compounds and intermediary metabolism: sulfoxidation bridges the divide.

It is widely appreciated that as a xenobiotic travels through an organism and interacts with the biochemical machinery of a living system, it most probably will undergo a number of metabolic alterations usually leading to a cluster of differing chemical species. Indeed, the modern 'metabonomic' approach, where earlier studied drug metabolism profiles have been reassessed, has indicated that there are normally many more previously unrecognised minor metabolites, and when all such biotransformation products are considered, then their total number is legion. It is now being recognised also that the same metabolic alteration of a substrate, especially a xenobiotic substrate, may be catalysed by more than one enzyme and that the previously sacrosanct notion of an enzyme's 'substrate specificity' may well be inverted to read a substrate's 'enzyme preference'. The following brief article attempts to highlight another aspect where our general acceptance of the 'status quo' needs to be reconsidered. The conventionally acknowledged division between the collection of enzymes that undertake intermediary metabolism and the group of enzymes responsible for xenobiotic metabolism may be becoming blurred. It may well be a prudent time to reassess the current dichotomous view. Overcoming inertia, with a realignment of ideas or alteration of perception, may permit new concepts to emerge leading to a more profound understanding and hopefully eventual benefits for mankind.

Sorption of Cm(III) and Gd(III) onto gibbsite, alpha-Al(OH)(3): A batch and TRLFS study.

Gd(III) and Cm(III) sorption onto a pure aluminum hydroxide, gibbsite (alpha-Al(OH)(3)), is studied by batch experiments and time-resolved laser fluorescence spectroscopy (TRLFS). The experiments are conducted under argon atmosphere to exclude the influence of atmospheric CO(2) on solution and surface speciation. Batch experiments are done in two different electrolytes 0.1 M NaClO(4) and 0.1/0.01 M NaCl at a constant gibbsite concentration of 2.2 g/L. Gadolinium concentrations are varied from 6.4x10(-9) to 6.4x10(-5) M. pH-dependent sorption is found to be congruent at Gd(III) concentrations up to 6.4x10(-7) M and a shift of the pH edge to higher pH values is observed for higher metal ion concentrations. Type of background electrolyte anion and ionic strength do not affect the metal ion sorption. The spectroscopic investigations are performed with Cm(III) and gibbsite concentrations of 2x10(-7) M and 0.5 g/L, respectively. From the strongly red-shifted emission spectra two different inner-sphere surface complexes can be identified. A third species appearing at pH 6-11 is assigned to a coprecipitated or incorporated Cm(III) species. This incorporated species is most likely formed as a consequence of the applied experimental procedure. By continuously increasing the pH from 4 we move from high to low gibbsite solubility domains. As a result, aluminum hydroxide precipitates from oversaturated solutions, either covering already adsorbed curium or forming a Al/Cm(OH)(3) coprecipitate. Fluorescence lifetimes for the surface-bound Cm(III) complexes and the incorporated species are at 140-150 and 180-200 micros, respectively. Emission bands of the Cm(III) gibbsite surface complexes appear at comparable wavelengths as reported for Cm(III) species bound to aluminum oxides, e.g., gamma-Al(2)O(3); however, lifetimes are longer. This could presumably arise from either shorter binding distances of the Cm to Al-O sites or a coordination to more surface sites.

Enzyme kinetic and molecular modelling studies of sulphur-containing substrates of phenylalanine 4-monooxygenase.

Previous investigations into the binding of substrates/cofactors to the PAH active site have only concentrated on Phe, thienylalanine and BH(4). This is the first reported investigation to model aliphatic thioether amino acid substrates to PAH. The clearance of the thioether substrates (4.82-79.09% of Phe) in the rat and human (1.19-37.41% of Phe) showed species differences. The xenobiotic thioether substrates (SMC and SCMC) were predicted to be poor substrates for PAH by the molecular modelling investigation and this has now been confirmed by the in vitro enzyme kinetic data. However, reaction phenotyping investigations have found that PAH was the major enzyme involved in the metabolism of SCMC in vitro and in vivo.

Flavin mono-oxygenase (FMO)--the 'other' oxidase.

Whilst the scientific community was celebrating the truly momentous discovery of a 'mixed function oxidase' another oxidase was quietly working behind the scenes, mopping up soft nucleophiles and, as it had undoubtedly being doing for aeons, aiding then unknown in the metabolism of xenobiotics and the protection of life forms. This enzyme, flavin mono-oxygenase, has subsequently been shown to be a major player, if not yet an equal partner with cytochrome(s) P450, in the metabolism of both endogenous biochemicals and foreign compounds that enter the human organism. This article outlines the importance of the flavin mono-oxygenases and examines their susceptibility to activity modulation by exogenous factors.

Dimethylamine and diet.

Forty-six different foods eaten by six healthy male volunteers were investigated as potential sources of the aliphatic secondary amine, dimethylamine. None that were representatives from the fruit and vegetable, meat, dairy and grain produce categories afforded any measurable elevation in urinary dimethylamine output following ingestion. All of the statistically significant increases occurred after consumption of fish and seafoods. However, within this category a wide variation was observed. The highest values were obtained for coley, squid and whiting with cod, haddock, sardine, skate and swordfish also producing substantial increases. Freshwater trout, plaice and prawns gave no discernable effect. It seems that not all fish and seafoods may be treated equally with regards to human dimethylamine exposure and that the situation is more complicated than at first appears.

Phenothiazine: the parent molecule.

Phenothiazine is an aromatic tricyclic compound that first emerged from the furtive chemical activity surrounding the aniline dye industry at the latter half of the 19th century. It contains both nitrogen and sulphur atoms and is the parent molecule of a multitude of drugs that have enjoyed varied and extensive use throughout medical and veterinary practice. The compound itself is not without biological activity and has been shown to possess insecticidal, antifungal, antibacterial and anthelmintic properties. It was this latter vermifugal application that has earned the molecule a place alongside penicillin and DDT for its colossal impact on mankind. Following its extensive usage over many years, unwanted reactions including neuromuscular incoordination, photosensitization and haemolytic anaemia have been reported and these have limited its use in the present climate. Investigations into the mode of action of phenothiazine and its underlying biochemical properties have been undertaken but the molecule has yet to reveal its secrets and still poses problems of understanding at the molecular level. This article reviews the literature, both established and current, and presents a contemporary view on phenothiazine and its interaction with biological systems.