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.     

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.     

Expression of LKB1 and PTEN tumor suppressor genes during mouse embryonic development.

Germ-line mutations of LKB1 and PTEN tumor suppressor genes underlie the phenotypically related Peutz-Jeghers syndrome (PJS) and Cowden disease (CD), respectively. To analyze possible developmental roles of PTEN and LKB1, we have studied their mRNA expression during mouse embryonic development (E7-17.5) by in situ hybridization. Ubiquitous expression of both genes during early stages (E7-11) became more restricted in later embryonic development (E15-19) where LKB1 and PTEN showed prominent overlapping expression in e.g. gastrointestinal tract and lung. In contrast, LKB1 was selectively expressed at high levels in testis and PTEN was prominently expressed in skin epithelium and underlying mesenchyme. These results indicate that LKB1 and PTEN display largely overlapping expression patterns during embryonic development. Moreover, a high expression of these genes was observed in the tissues and organs affected in PJS and CD patients and in PTEN+/- mice.     

Urinary excretion of prostacyclin and thromboxane metabolites in climacteric women: effect of estrogen-progestin replacement therapy

To study the role of vasodilatory prostacyclin and vasoconstrictory thromboxane A2 in climacteric vascular instabilities, overnight urine samples were collected from sixteen women suffering from hot flushes and sweating before, during and after the six months' cyclic estradiol-desogestrel therapy as well as from ten non-climacteric control women. The urine was assayed for 6-keto-PGF1a and 2,3-dinor-6-keto-PGF1a (metabolites of prostacyclin) as well as for thromboxane B2 and 2,3-dinor-thromboxane B2 (metabolites of thromboxane A2) by means of HPLC and radioimmunoassay. No difference was seen in baseline prostaroid output between the climacteric and non-climacteric study groups. Furthermore, no relation was observed between individual prostanoid excretion and severity of vasomotor symptoms before replacement therapy. The replacement therapy abolished or markedly alleviated hot flushes and sweating, but prostanoid output did not change. Our data imply that climacteric symptoms are not accompanied by changes in the production of prostacyclin and thromboxane A2.     

Cold-Induced Freezing Tolerance in Arabidopsis

Changes in the physiology of plant leaves are correlated with enhanced freezing tolerance and include accumulation of compatible solutes, changes in membrane composition and behavior, and altered gene expression. Some of these changes are required for enhanced freezing tolerance, whereas others are merely consequences of low temperature. In this study we demonstrated that a combination of cold and light is required for enhanced freezing tolerance in Arabidopsis leaves, and this combination is associated with the accumulation of soluble sugars and proline. Sugar accumulation was evident within 2 h after a shift to low temperature, which preceded measured changes in freezing tolerance. In contrast, significant freezing tolerance was attained before the accumulation of proline or major changes in the percentage of dry weight were detected. Many mRNAs also rapidly accumulated in response to low temperature. All of the cold-induced mRNAs that we examined accumulated at low temperature even in the absence of light, when there was no enhancement of freezing tolerance. Thus, the accumulation of these mRNAs is insufficient for cold-induced freezing tolerance.     

Gibberellin mediates daylength-controlled differentiation of vegetative meristems in strawberry (Fragaria × ananassa Duch)

Background  

Differentiation of long and short shoots is an important developmental trait in several species of the Rosaceae family. However, the physiological mechanisms controlling this differentiation are largely unknown. We have studied the role of gibberellin (GA) in regulation of shoot differentiation in strawberry (Fragaria × ananassa Duch.) cv. Korona. In strawberry, differentiation of axillary buds to runners (long shoot) or to crown branches (short shoot) is promoted by long-day and short-day conditions, respectively. Formation of crown branches is a prerequisite for satisfactory flowering because inflorescences are formed from the apical meristems of the crown.