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Biomedical subjects

O Pelkonen

Publications and source records attributed to O Pelkonen.

At least 199 records · Page 11Linked to original sources
PubMed1980

Environmental influences on human foetal and placental xenobiotic metabolism.

The human foetus is more capable of metabolizing xenobiotics than foetuses of common laboratory animal species. However, xenobiotic metabolism in animal foetuses is inducible by the exposure of the mother to various inducers during late pregnancy. Xenobiotic metabolism in neonates is more easily inducible than in foetal animals. With respect to the human foetus at mid-pregnancy, the hepatic enzyme systems do not seem to be readily inducible by exoaenous inducers, whereas the placental monooxygenase system is almost totaly dependent on maternal cigarette smoking. In the human newborn, indirect evidence points to the possibility of induction by potential inducers. The ontogenetic development of xenobiotic metabolism is probably regulated by endogenous hormones. It is possible that environmental factors may effect these normal regulatory and "imprinting" phenomena and thus lead to permanent disturbances in xenobiotic metabolism.

Animals↗
PubMed1980

Effect of cimetidine on microsomal drug metabolism in man.

The effect of cimetidine on human microsomal drug metabolism was studied. In five of six healthy volunteers therapeutic doses of cimetidine prolonged the half-life of antipyrine (range 12-37%; p < 0.05). Its clearance was decreased in five subjects (range 2-18%) and was increased in one subject (15%), the changes not being statistically significant. The volume of distribution increased on average by about 14% (range 9--19%; p < 0.001). Cimetidine in vitro inhibited the hydroxylation of benzo(a)pyrene and coumarin, as well as the O-deethylation of 7-ethoxycoumarin, by homogenised liver biopsies. The in vitro studies suggest that the effect of cimetidine on antipyrine elimination is due to inhibition of microsomal drug metabolism, which may prove an important drug interaction.

Adult↗
PubMed1980

Unusual patterns of benzo[a]pyrene metabolites and DNA-benzo[a]pyrene adducts produced by human placental microsomes in vitro.

Human placental microsomes were incubated with [3H]benzo[a]pyrene (BP) and Salmon sperm DNA and the resulting metabolite-nucleoside complexes resolved by Sephadex LH-20 chromatography. The metabolite pattern was analyzed by high-pressure liquid chromatography (HPLC). The incubates were also co-chromatographed with extracts obtained from incubates with rat liver microsomes and [14C] BP. Phenols, quinones and 7,8-dihydrodiol were detected in the placental incubates. Both 9,10- and 4,5-dihydrodiols were very low as compared with control rat liver samples. Placental microsomes catalyzed the binding of BP metabolites to DNA in vitro, giving rise to two main complexes which co-chromatographed with rat liver-produced peaks attributable to 7,8-diol-9,10-epoxide and 7,8-oxide and/or quinones when metabolized further. The nucleoside metabolite peaks attributable to 4,5-oxide and 9-phenol-4,5-oxide were lacking when compared with the binding pattern catalyzed by rat liver. Both the total binding and specific metabolite-nucleoside adducts in the placenta correlated with fluorometrically measured aryl hydrocarbon hydroxylase (AHH) activity and with the amount of dihydrodiol formed. The results demonstrate that both the metabolite pattern and the nucleoside-metabolite complexes formed by the placental microsomes in vitro differed greatly from thos produced by rat liver microsomes. These sstudies also suggest that it is not possible to predict specific patterns of DNA binding from AHH measurements or even from BP metabolite patterns, especially when comparing different tissues and species.

Aryl Hydrocarbon Hydroxylases↗
PubMed1980

DNA binding of benzo[a]pyrene metabolites. Effects of substrate and microsomal protein concentration in vitro, dietary contaminants, and tissue differences.

The binding of reactive benzo[a]pyrene metabolites to deproteinized DNA in vitro can be drastically changed, both quantitatively and qualitatively, in vitro by changes in the substrate concentration or the substrate/P-450 ratio, and in the intact animal by starvation or substitution of a 'purified protein test diet' for the regular laboratory chow. Liver, lung, and bowel microsomes from C57BL/6N and DBA/2N mice were examined. These data demonstrate the importance of dietary contaminants or nutrition during benzo[a]pyrene tumorigenesis. The profile of DNA binding of benzo[a]pyrene metabolites is also shown to be an extremely sensitive test for detecting minute amounts of induced cytochrome P1-450 and its associated aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2) activity. A direct correlation is not necessarily observed, however, between 'aryl hydrocarbon hydroxylase activity' and the amount of benzo[a]pyrene metabolites bound covalently to DNA. 'Untreated' genetically responsive mice are shown to have greater 'control' levels of benzo[a]pyrene metabolism in their various tissues than genetically nonresponsive mice simply on the basis that responsive mice have a lower threshold for 'responsiveness' to exogenous inducers inhaled and/or ingested in their crude diet, i.e., responsive 'control' animals already have partially induced enzymes.

Animals↗
PubMed1979

Effects of various in vitro--inhibitors of benzo(a)pyrene metabolism in isolated rat lung perfusion.

Various in vitro-inhibitors were added with 3H-benzo(a)pyrene (BP) into the perfusion fluids in isolated rat lung perfusions to see whether their effects are dependent on the integrity of tissue. 3H-BP and its metabolites were measured by thin-layer chromatography and radiometry from both samples of perfusion medium and homogenates of lung tissue. The total covalent binding to lung tissue was used as a measure of the formation of reactive metabolites. In methylcholanthrene-induced rat lung, the metabolism of BP was inhibited by alpha-naphthoflavone, an inhibitor of monooxygenase, and less with diethylmaleate, a depletor of glutathione, with salicylamide, an inhibitor of conjugases, and, astonishingly, with D-saccharo-1,4-lactone, an inhibitor of beta-glucuronidase. With trichloropropene oxide, which inhibits epoxide hydratase, the metabolism was either decreased or unchanged. Nicotine had no effect on BP-metabolism. Nicotine and diethylmaleate increased statistically significantly and alpha-naphthoflavone and salicylamide decreased the covalent binding of radioactivity to lung tissue. In most cases, the changes in BP metabolism observed during perfusion can be explained on the basis of effects of modifiers on the enzyme systems.

Animals↗