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O Pelkonen

Publications and source records attributed to O Pelkonen.

241 records · Page 14Linked to original sources
PubMedDate not supplied

Styrene metabolism by cDNA-expressed human hepatic and pulmonary cytochromes P450.

The rate of formation of styrene glycol from styrene was compared in human, rat, and mouse liver microsomes. At a low styrene concentration (0.085 mM), the rates decreased in the order, mouse (2.43 +/- 0.29 nmol/(mg of protein.min)) > rat (1.07 +/- 0.20) > human (0.73 +/- 0.45); at a high concentration (1.85 mM), the order was rat (4.21 +/- 0.72) > mouse (2.72 +/- 0.11) > human (1.91 +/- 0.84). Kinetic analysis indicated the presence of at least two forms of styrene-metabolizing cytochrome P450s with different Km values in human liver microsomes. Styrene was also metabolized in human lung microsomes: the rate of styrene glycol formation was higher in the lung microsomes from smokers than in those from current nonsmokers. The P450 forms responsible for transforming styrene to styrene glycol were determined by analyzing cDNA-expressed individual P450 forms produced in cultured hepatoma G2 cells by recombinant vaccinia viruses. Of the 12 human P450 forms studied, CYP2B6 and CYP2E1 existing in human liver and/or lungs and CYP2F1 in human lungs were the most active in the forming of styrene glycol, followed by CYP1A2 and CYP2C8. Human CYP3A3, CYP3A4, CYP3A5, and CYP4B1 also catalyzed the metabolism but were much less active. CYP2A6, CYP2C9, and CYP2D6 had only a little detectable activity. CYP1A2, CYP2B6, CYP2C8, CYP2E1, and CYP3A4/3A3 were expressed in human liver microsomes, and CYP2C8 was expressed in human lung microsomes, although the expression of CYP2F1 and CYP4B1 could not be investigated. These data indicate that several human hepatic and/or pulmonary P450 forms are capable of metabolizing styrene, albeit at different rates.

Adult↗
PubMedDate not supplied

Antepartum glucocorticoid therapy suppresses human placental xenobiotic and steroid metabolizing enzymes.

We investigated the effects of maternal gestational corticosteroid therapy on placental xenobiotic and steroid metabolizing enzymes at term in 20 glucocorticoid/betamethasone treated (with various doses) and control (n=10) women. A single dose of betamethasone (12 mg i.m. twice at a 24-h interval) was given to 15 mothers at risk of preterm delivery to prevent respiratory syndrome in their premature newborns. Five mothers were treated more than once. The gestation time in mothers receiving the glucocorticoid therapy varied from 22-38 gestational weeks. Compared with controls, a significant decrease in placental aromatase activity (53.6+/-18.0 pmol/mg/min versus 119+/-30 pmol/mg/min, P=0.0007) and placental CYP19 mRNA content (by 50 per cent ) was observed in mothers treated with glucocorticoids. Also the formation of androstenedione (13.2+/-8.1 pmol/mg/min, steroids versus 30.03+/-5.2 pmol/mg/min, controls, P< 0.001), using testosterone as the substrate, and 7-ethoxycoumarin O-deethylase (P< 0.05) and 7-ethoxyresorufin O-deethylase (P< 0.09) were slightly decreased in the glucocorticoid treated compared to control patients' values. The changes were not dependent on the number of treatments or the time between treatment and delivery. Our results demonstrate that even a single dose of glucocorticoid given to expectant mothers is associated with diminished placental steroid hormone and xenobiotic metabolizing enzymes at term. Further studies are needed to assess whether these changes affect the well-being of the fetus and its later development.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Metabolic activation and inactivation of chemical carcinogens.

Chemical carcinogens are metabolized by numerous pathways catalyzed by enzymes in endoplasmic reticulum and other parts of the cell. Reactions in which functional groups are created (epoxidation and epoxide hydration, catalyzed by cytochrome P-450-linked monooxygenase and epoxide hydratase, respectively) are especially important in the activation of polycyclic hydrocarbon carcinogens to ultimate carcinogenic forms, although other enzymes may also participate in the activation of other chemical carcinogens. Numerous factors, genetic as well as environmental, affect the activities and the balance of different enzymes that participate in carcinogen activation and detoxification. The reasons why carcinogens act on specific target tissues are incompletely understood, although differences in enzyme profiles between tissues certainly contribute to the target tissue variability. Also, the location in the cell (endoplasmic reticulum, nuclear membrane, or other organelle) where the activation takes place is not known. It has been demonstrated that conjugated metabolites of carcinogens may be activated by spontaneous or enzymatic hydrolysis, and this raises the possibility of transport of metabolites to distant target tissues. The concept of metabolic activation of carcinogens by body's own enzymes has led to the development of short-term assay systems, which essentially measure the production of biologically active metabolites from potential carcinogens.

Animals↗
PubMedDate not supplied

Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxcarbazepine.

We evaluated liver P450 enzyme system induction and serum lipid levels in a prospective follow-up study in 12 male patients with epilepsy after replacing carbamazepine (CBZ) medication with oxcarbazepine (OCBZ). Antipyrine(t1/2) increased and antipyrine(CL) decreased 2 months after the medication was changed, reflecting normalization of liver P450 enzyme system function. Furthermore, serum total cholesterol levels decreased, but serum concentrations of high-density lipoprotein (HDL)-cholesterol and triglycerides (TG) were unchanged. OCBZ may be the preferable antiepileptic drug (AED) with regard to the effects of the medication on lipid metabolism.

Adult↗
PubMedDate not supplied

Correlations between cytochrome P-450 and oxidative metabolism of benzo[a]pyrene and 7-ethoxycoumarin in human liver in vitro and antipyrine elimination in vivo.

Cytochrome P-450 content was correlated to aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-de-ethylase activities in human liver biopsy samples in vitro. Antipyrine half-life and clearance were measured in the same patients in vivo. The results were compared with data obtained in rat liver in vitro. The correlation of cytochrome P-450 content with aryl hydrocarbon hydroxylase activity in human liver biopsy samples was relatively good (r = 0.75, p < 0.001), but that with 7-ethoxycoumarin O-de-ethylase activity was much poorer (r = 0.42, p < 0.001). The good correlation between cytochrome P-450 content and aryl hydrocarbon hydroxylase activity in biopsy samples from patients with widely varying hepatic disease processes, exposure to inducers, history of cigarette smoking, etc., is in contrast with the data obtained in the rat, where the corresponding correlation in a population treated with different inducers and inhibitors was rather poor (r = 0.37, p < 0.01). This poor correlation was caused mainly by the nonequal effects of polycyclic aromatic hydrocarbons on cytochrome P-450 and aryl hydrocarbon hydroxylase. Cigarette smoking was not found to induce human liver drug or carcinogen metabolism. Aryl hydrocarbon hydroxylase activity in vitro and antipyrine half-life or clearance in vivo were correlated (r = 0.36, p < 0.01 and r = 0.35, p < 0.01, respectively), indicating a weak, but statistically significant association between these parameters. This study suggests that correlations between in vitro and in vivo measurements of drug metabolism are not strong enough for the tests to be used as predictive tests in experimental or clinical research.

7-Alkoxycoumarin O-Dealkylase↗