Hepatocytes: the powerhouse of biotransformation

Liver is the most important organ involved in biotransformation of xenobiotics. Within the main organisational unit, the hepatocyte, is an assembly of enzymes commonly classified as phase I and phase II enzymes. The phase I enzymes principally cytochrome P450 catalyse both oxidative and reductive reactions of a bewildering number of xenobiotics. Many of the products of phase I enzymes become substrates for the phase II enzymes, which catalyse conjugation reactions making use of endogenous cofactors. As xenobiotic metabolising enzymes are responsible for the toxicity of many chemicals and drugs, testing the role of the biotransformation enzymes and the transporters within the hepatocyte is critical. New methodologies may be able to provide information to allow for better in vitro to in vivo extrapolation of data.     

A Genetic Polymorphism in Coumarin 7-Hydroxylation: Sequence of the Human CYP2A Gnes and Identification of Variant CYP2A6 Alleles

A group of human cytochrome P450 genes encompassing the CYP2A, CYP2B, and CYP2F subfamilies were cloned and assembled into a 350-kb contig localized on the long arm of chromosome 19. Three complete CYP2A genes—CYP2A6, CYP2A7, and CYP2A13—plus two pseudogenes truncated after exon 5, were identified and sequenced. A variant CYP2A6 allele that differed from the corresponding CYP2A6 and CYP2A7 cDNAs previously sequenced was found and was designated CYP2A6ν2. Sequence differences in the CYP2A6ν2 gene are restricted to regions encompassing exons 3, 6, and 8, which bear sequence relatedness with the corresponding exons of the CYP2A7 gene, located downstream and centromeric of CYP2A6ν2, suggesting recent gene-conversion events. The sequencing of all the CYP2A genes allowed the design of a PCR diagnostic test for the normal CYP2A6 allele, the CYP2A6ν2 allele, and a variant—designated CYP2A6ν1—that encodes an enzyme with a single inactivating amino acid change. These variant alleles were found in individuals who were deficient in their ability to metabolize the CYP2A6 probe drug coumarin. The allelic frequencies of CYP2A6ν1 and CYP2A6ν2 differed significantly between Caucasian, Asian, and African-American populations. These studies establish the existence of a new cytochrome P450 genetic polymorphism.     

Infertile times: response to damage in genets of the clonal sedge Carex bigelowii

Tolerance to grazing is a plant trait that can be adaptive in systems where plants are subjected to a diversity of herbivore attack types. To test the tolerance ability of the clonal sedge Carex bigelowii, which is food plant to several herbivores in alpine and arctic areas, and the potential fitness costs of this tolerance, replicated units of genets were subjected to three levels of damage throughout three consecutive seasons. The three levels of treatment were no damage, light damage and heavy damage, and the damage was conducted by tearing off all plant material at 3 and 0 cm above-ground respectively. The genets had no tolerance under damage in terms of sexual reproduction. In terms of clonal reproduction the genets showed tolerance under light damage but not under heavy damage. However, no fitness cost was found for this tolerance ability, i.e. genets had higher reproduction and growth under no damage. The average ramet weight had a similar decrease under both a low and high damage treatment. Changed partitioning of biomass between plant parts and reduced concentration of total non-structural carbohydrates (TNC) in storage organs are possible mechanisms for the ability to uphold clonal reproduction in response to damage. There were no significant indications that tolerance ability or its fitness cost differed between genets. Our results suggest that when subjected to heavy damage genets will only reproduce vegetatively. Consequently, it seems C. bigelowii has evolved to allocate resources to the survival of an already successful genet rather than to a potential new genet of unknown success.     

Effect of physicochemical and pharmacokinetic properties of barbiturates on the induction of drug metabolism

In searching for possible determinants of the ability of compounds to induce microsomal drug metabolizing enzymes we studied relationships between the relative inducing activity of eleven barbiturates and their lipid solubility and pharmacokinetic behaviour. Allyl derivatives of barbituric acid were poor inducers regardless of their lipid solubility or half-life. The ability of other barbiturate derivatives to induce drug metabolism was directly related to biological half-life or time/concentration area value and inversely correlated to lipid solubility. The results suggest that the ability of a given compound to induce drug metabolism is not only related to lipid solubility and pharmacokinetic characteristics but also to the nature of chemical groups present in the molecule.     

Decomposition Analysis of Finnish Material Flows: 1960–1996

To the extent that environmental impacts are the consequence of the magnitude of total material input into production in an economy, they can be lessened by reducing the use of materials—by concentrating on what has been called qualitative growth. This article presents a summary of Finnish resource use over the period 1960–1996 as a means of evaluating the trends in material use and providing a basis for assessments of sustainability. It adapts the technique of decomposition analysis developed in the field of energy studies to distinguish the effects of changes in aggregate economic activity ("activity effect"), composition of industrial activity ("structural effect") and materials intensity of use ("intensity effect") on a sectoral basis.p
According to the analysis presented here, materials consumption in Finland has grown substantially between 1960 and 1996 in the electricity, gas and water supply, pulp and paper production, civil engineering, and mining and quarrying sectors. In the same period, the ratio of GDP/mass of material mobilized has improved by 175 percent. Economic growth has caused the largest increases in materials use in the building of infrastructures; for example roads, waterways, means of supplying electricity, gas, and water, and in the production of paper and paper products. The least growth took place in the transport, basic metals production, and mining and quarrying sectors.