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O Pelkonen

Publications and source records attributed to O Pelkonen.

At least 163 records · Page 9Linked to original sources
PubMed1987

Mutagenicity studies of different polycyclic aromatic hydrocarbons: the significance of enzymatic factors and molecular structure.

Dependence of polycyclic aromatic hydrocarbon (PAH)-induced mutagenicity on the bay region of the molecule and on the activating cytochrome P-450 enzyme was studied. Eleven PAHs with and six without a bay region were activated by postmitochondrial supernatants from control and 3-methylcholanthrene (MC)-pretreated C57BL/6 mice and from control, MC- and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-pretreated DBA/2 mice and from control and MC-pretreated Sprague-Dawley and Lewis rats. S-9 fractions from MC- or TCDD-treated animals induced more mutagenicity with PAHs with a bay region compared with S-9 fractions from control animals or MC-treated D2 mice. Mutagenicities of PAHs without a bay region were largely independent of the source of activating enzyme. There were three exceptions, namely benzo[e]pyrene, phenanthrene and perylene (each possessing a bay region), which were not mutagenic. These studies support the notion that the Ah-locus-controlled induction of cytochrome P1-450 activating PAHs into reactive intermediates at the bay region of the hydrocarbon molecule is of prime importance in the mutagenicity of PAHs. Qualitative correspondence to carcinogenicity is also apparent.

Animals↗
PubMed1987

Characterization of human fetal hepatic cytochrome P-450-associated 7-ethoxyresorufin O-deethylase and aryl hydrocarbon hydroxylase activities by monoclonal antibodies.

Two cytochrome P-450-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE) and aryl hydrocarbon hydroxylase (AHH) were measured in liver microsomes from 7 human fetuses. Monoclonal antibodies (MAb) to a 3-methylcholanthrene-induced (MAb 1-7-1) and a phenobarbital-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of the MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for the above activities. MAb 1-7-1 inhibited fetal hepatic ERDE activity to a variable extent (from 0 to 100%, 34 in average), but had only negligible effects on AHH activity (mean inhibition 9%). The contribution of induction by cigarette smoking to the variability of ERDE inhibition by MAb 1-7-1 remained unclear. MAb 2-66-3 inhibited ERDE activity by 18% and AHH activity by 12%. In comparisons with earlier studies on adult liver and placental microsomes, the present results with fetal liver suggest that there are differences in cytochrome P-450-associated ERDE and AHH activities between these tissues, which might be due to different tissue-specific isoenzyme patterns.

Antibodies, Monoclonal↗
PubMed1986

Effect of five structurally diverse H2-receptor antagonists on drug metabolism.

Some H2-receptor antagonists can interact with the biotransformation of other drugs. This is due to their binding to cytochrome P-450. We tested the in vitro effects of 5 different H2-receptor antagonists cimetidine (C), oxmetidine (O), ranitidine (R), famotidine (F) and nizatidine (N) on arylhydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase and 7-ethoxy-resorufin-O-deethylase activity using liver microsomes from man as well as from untreated, phenobarbital and 3-methylcholanthrene treated rats. In addition their binding to human microsomal cytochrome P-450 was evaluated. The in vivo effects of these antagonists were investigated on the hepatic elimination of diazepam in healthy volunteers. In vitro O was found to be the most effective inhibitor of the enzyme activities studied. C showed a clear inhibitory effect only with rat liver microsomes whereas the remaining drugs were more than 10 times less potent. The binding affinities of these antagonists showed a similar tendency: the Ks-values for O, C and R were 0.2, 0.9 and 5.1 mM, respectively; for F and N no binding up to 4 mM could be observed. However, in man, only C inhibited the hepatic elimination of diazepam by about 45% while R, O, N and F did not affect the pharmacokinetics of diazepam. Thus, it could be concluded from our studies that one cannot extrapolate in vitro data of the inhibitory potency of H2-receptor antagonists in every case to human in vivo drug metabolism.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

Purification and immunological characterization of human placental mitochondrial cytochrome P-450.

Human placental mitochondrial cytochrome P-450 was purified to electrophoretic homogeneity by hydrophobic, anion exchange and cation exchange column chromatography. The specific content of the purified protein was 15.7 nmol/mg protein and it showed a single band mol. wt 48,000 D in SDS-gel electrophoresis. When reconstituted with bovine adrenal adrenodoxin reductase and adrenodoxin it converted cholesterol to pregnenolone (cholesterol side-chain cleavage activity, CSCC) at the rate of 1 pmol/min/pmol P-450. Antibodies against the purified protein were raised in rabbits. Inhibition studies demonstrated 85% inhibition of placental CSCC activity at an antibody/protein ratio of 10:1. Placental microsomal aromatase activity was inhibited by 47% at the same antibody/protein ratio. The antibody inhibited bovine mitochondrial CSCC activity by 87% at the same antibody/protein ratio. Placental microsomal 7-ethoxycoumarin O-deethylase, aryl hydrocarbon hydroxylase and 7-ethoxyresorufin O-deethylase activities were not significantly inhibited by the antibody. The results indicate that the purified protein catalyzes cholesterol side-chain cleavage reaction, human placental microsomal aromatase and bovine adrenal mitochondrial P-450scc may share common antigenic determinants with placental P-450scc, but the placental microsomal xenobiotic-metabolizing cytochrome(s) is (are) distinctly different.

Adrenal Glands↗
PubMed1986

The effect of cigarette smoking on 7-ethoxyresorufin O-deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

Four cytochrome P-450 enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE), coumarin 7-hydroxylase (CH), 7-ethoxycoumarin O-deethylase (ECDE) and aryl hydrocarbon hydroxylase (AHH) were measured in human liver needle biopsy samples from smokers and non-smokers. Cigarette smoking was verified and quantitated by measuring plasma cotinine levels. Enzyme inhibitory monoclonal antibodies (MAb) to a 3-methylcholanthrene-induced (MAb 1-7-1) and phenobarbitone-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for each of the above activities. ERDE activity was significantly elevated in the livers of cigarette smokers, whereas AHH, CH or ECDE activities were not affected by cigarette smoking. No correlation was observed between plasma cotinine concentration and ERDE activity. MAb 1-7-1 inhibited hepatic ERDE activity to a variable extent (from 0 to 65%), but had very little or no effect on AHH, CH or ECDE activities. The inhibitory effect of MAb 1-7-1 on ERDE activity was greater than 50% in the non-smokers. MAb 2-66-3 had no inhibitory effect on any of the enzyme activities studied. In contrast to liver both ERDE and AHH on human placental microsomes from cigarette smokers were inhibited by MAb 1-7-1. The MAb 2-66-3 was without effect. Cigarette smoking induces a form of P-450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1-7-1. This form of cytochrome P-450 is insensitive to MAb 2-66-3 and is not contributing to AHH, CH or ECDE activities of human liver.

Antibodies, Monoclonal↗
PubMed1986

Host susceptibility in organic solvent toxicity.

The importance of host factors, both genetic and nongenetic, is evident in the actions of foreign chemicals. Host factors may act at both toxicodynamic and toxicokinetic levels. Perhaps the best understood phase of influence is the metabolism of foreign substances, which displays enormous interindividual variation. Genetic, non-genetic and environmental factors are known to be behind this variation, although it is not always in real life easy to tell the relative importance of these different factors. With respect to organic solvent toxicity, there are very little data about the significance of host factors. It is possible, however, that host susceptibility is of critical importance in delayed toxic manifestations of halogenated organic solvents. This view is based mainly on animal experiments.

Animals↗
PubMed1985

Resolution of multiple P-450 forms: separation of aryl hydrocarbon hydroxylase and aminopyrine N-demethylase-associated P-450 isoenzymes by chromatofocusing.

Chromatofocusing between pH 7.4 and 5.0 was introduced as a final step for the resolution of multiple forms of cytochrome P-450 from control, phenobarbital and 3-methylcholanthrene-pretreated rat liver microsomal fractions. Altogether, chromatofocusing produced 21 P-450-containing pools, which differed from each other with respect to substrate specificity, spectral maximum and elution pH. Aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) activity was concentrated into low pI pools in all animal groups. 7-Ethoxycoumarin O-deethylase (ECOD) activity comigrated with AHH activity throughout the purification procedure. Aminopyrine N-demethylase (APND) activity was spread into several pools with forms of both low and high pI proteins.

Aminopyrine N-Demethylase↗
PubMed1985

Ovarian toxicity of cigarette smoke exposure during pregnancy in mice.

Pregnant mice of C57BL/6 and DBA/2 inbred strains were exposed to cigarette smoke during days 1-18 of pregnancy. Both mothers and offspring were killed at the age of 21-22 weeks, and ovaries were studied with respect to the number of primordial follicles and small primary follicles. In additional studies, 7,12-dimethylbenz(a)anthracene (DMBA) was administered on day 15 of pregnancy. Cigarette-smoke exposure during gestation did not affect the number of primordial follicles in the ovaries of mothers, whereas counts were significantly decreased (31%) in the ovaries of DBA/2 offspring, and decreased, although not significantly (20%) in the ovaries of C57BL/6 offspring. DMBA (5 to 50 mg/kg) decreased oocyte counts in the mothers in a dose-dependent manner. At the same doses, DMBA reduced the viability of the offspring. These studies suggest that primordial and small primary follicles may be more sensitive to components in cigarette smoke during fetal life than in adulthood.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Passive and active exposure to cigarette smoke in a smoking experiment.

Six volunteer female habitual smokers were exposed during a 2-wk experimental period to cigarette smoke, both actively and passively, in an exposure chamber (volume 10 m3, average air exchange rate 6.8 times/h), where the ambient carbon monoxide, particle, and aldehyde concentrations were monitored. Three of the six subjects were smoking at the time, 2 cigarettes (filtered, self-burning low tar brand) per person per hour, 30 cigarettes altogether during each of the 5-h experimental days in the chamber. Samples of blood and urine were taken from each subject after 3 nonsmoking days and after each day of active or passive smoking. Among the parameters tested, blood carboxyhemoglobin, plasma cotinine, and urinary mutagenicity were higher in samples taken after active smoking than after nonsmoking periods. Although the exposure conditions were similar for all subjects, the parameters measured showed quite high interindividual variation. Thioethers and thiocyanates were not significantly elevated in the active smoking samples; neither were there any differences during this short experimental period in the sister chromatid exchange frequencies. The only parameters showing an increasing trend after passive exposure, as compared with nonsmoking samples, were urinary mutagenicity and plasma cotinine, the main metabolite of nicotine.

Adult↗
PubMed1985

Coumarin 7-hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Coumarin 7-hydroxylation and other cytochrome P-450-associated enzyme activities were studied in human liver biopsy homogenates and compared with activities in livers of other species. Coumarin 7-hydroxylation is extraordinarily active in human liver biopsy samples in vitro. Activity is lower in mouse, rabbit or guinea pig liver and essentially absent in rat liver. Cytochrome P-450 content and other associated enzyme activities were higher in animals. Coumarin 7-hydroxylation is induced by phenobarbitone in mouse liver, but no significant increase was seen in human or rat liver after exposure to inducers. Correlations amongst coumarin 7-hydroxylase, aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase and cytochrome P-450 are statistically significant (r values from 0.56 to 0.73), but do not permit the conclusion, that the same P-450 form catalyzes all the reactions studied. The correlations between coumarin hydroxylation and antipyrine half-life or clearance are statistically significant, but not good enough for predictive purposes. Coumarin 7-hydroxylase in human liver is inhibited by alpha-naphthoflavone, SKF 525A, metyrapone and aniline.

Animals↗
PubMed1984

Cholesterol side-chain cleavage activity in human placenta and bovine adrenals: an one-step method for separation of pregnenolone formed in vitro.

Cholesterol side-chain cleavage (CSCC) activity towards exogenous cholesterol was quantified by an one-step reversed-phase minicolumn method for the separation of pregnenolone formed in the reaction. The assay is rapid and reproducible. The method is linear for up to 2 mg of placental mitochondrial protein and up to 1 mg of bovine adrenal mitochondrial protein in the incubata over 30 min and 5 min reaction times, respectively. Average Km and Vmax values were 14.1 microM and 3.4 pmol/min/mg for the placental preparation and 1.5 microM and 20.7 pmol/min/mg for the bovine adrenal mitochondrial preparation. In human placenta, the mitochondrial fraction contained most of the CSCC activity. Inhibition studies showed that aminoglutethimide (500 microM) inhibited both placental and bovine adrenal activities at the same level (about 80-90% inhibition) but androstenedione (500 microM), metyrapone (500 microM), benzo(a)pyrene (800 microM) and Emulgen 911 (0.05%) were more effective in human placental preparations. Neither of the activities were inhibited to any great extent by alpha-naphthoflavone (500 microM), SKF 525A (500 microM) or 7-ethoxycoumarin (1 mM).

Adrenal Glands↗
PubMed1984

Genetic and environmental regulation of aryl hydrocarbon hydroxylase in man: studies with liver, lung, placenta, and lymphocytes.

Properties and response smoking of aryl hydrocarbon hydroxylase (AHH) activity in various human tissues are reviewed. In the placenta, induction of AHH by smoking can be demonstrated unequivocally. AHH activity in lung samples is variable, but the relation to current or past smoking is unclear. The effect of cigarette smoking can be readily shown in the rate of antipyrine elimination, although there is no change in AHH activity in liver biopsy samples. The reason for this discrepancy is not known. In peripheral lymphocytes a sort of "memory-effect" of cigarette smoking is retained even after culturing, the nature of this phenomenon remaining unclear. Furthermore, there seem to be many factors affecting AHH induction in peripheral lymphocytes in culture. These data suggest that regulation of AHH activity and induction is tissue-specific, i.e. no systemic regulation is discernible. It is also possible that the P-450 isozyme composition in some tissues masks the induction. Reasons for discrepancies between animal and human data are not clear; however, genuine biological differences and technical difficulties in human studies can be postulated.

Animals↗
PubMed1983

Metoclopramide and breast feeding: transfer into milk and the newborn.

The pharmacokinetics and endocrinological effects of metoclopramide were investigated in 5 mothers with deficient lactation and in their children soon after delivery. In addition, the transfer of metoclopramide into breast milk was evaluated in 18 mothers during the 8th to 12th puerperal weeks. Metoclopramide was detected in all the milk samples studied, generally at a higher concentration than in maternal plasma. Metoclopramide was found in plasma from only 1 of the 5 neonates studied. Exposure of the child to metoclopramide, estimated by multiplying the daily breast milk volume by the concentration of metoclopramide in the milk, ranged from 6 to 24 micrograms/kg/day for the 5 children in the early puerperium to 1 to 13 micrograms/kg/day for the 18 children during the late puerperium. These quantities are considerably less than the therapeutic dose of 500 micrograms/kg/day recommended for children. However, the plasma concentration of prolactin in 4 out of 7 neonates sampled taken during administration of metoclopramide to the mother were higher than the highest plasma prolactin level in children of same age of untreated mothers. The plasma concentration of thyrotrophin in the newborns remained within the normal range.

Female↗