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Markku Pasanen

Publications and source records attributed to Markku Pasanen.

10 recordsLinked to original sources
PubMed2006

Polycyclic aromatic hydrocarbon (PAH) metabolizing enzyme activities in human lung, and their inducibility by exposure to naphthalene, phenanthrene, pyrene, chrysene, and benzo(a)pyrene as shown in the rat lung and liver.

In order to survey changes and activities in the polycyclic aromatic hydrocarbon (PAH)-metabolizing enzymes implicated in lung cancer susceptibility studies, we investigated enzyme induction by 2-5-ring-sized 'biomarker' PAHs in rat liver and lung, and the activities in five human lung specimens. Naphthalene, phenanthrene, pyrene, chrysene, and benzo[a]pyrene (BaP) were administered to rats for 3 days (25-128 mg/kg/day) and the responses compared with those of model inducers. PAH treatment increased the CYP1A-catalyzed activity of pyrene 1-hydroxylation and 7-ethoxyresorufin O-deethylation in rat liver by up to 28- and 279-fold, and in rat lung by up to 22- and 51-fold, respectively. 1-Naphthol (hUGT1A6), 1-hydroxypyrene (hUGT1A6/1A9), and entacapone (hUGT1A9) are markers of PAH-glucuronidating human uridine diphosphate-glucuronosyltransferases (UGT). These activities increased up to 6.4-fold in rat liver and up to 1.9-fold in rat lung. NADPH:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase activities increased up to 5.3- and 1.6-fold (liver), and up to 4.4- and 1.4-fold (lung), respectively. CYP1A showed the best liver-to-lung relationship (R (2 )=( )0.90). The inducing efficiency by PAHs differed extensively: control 60-fold), many times greater than the experimental (inducible/constitutive) variation in the rat. Kinetics of 1-hydroxypyrene glucuronidation showed two low-K (m) forms both in rat and human lung. Since the 2-4-ring PAHs (major constituents) were poor enzyme inducers, it appears that the PAH-metabolizing pathways are mainly induced by BaP-type minor constituents. Gene-environmental interactions which magnify polymorphic variability in pulmonary bioactivation/detoxification capacity probably play a key role in individual susceptibility to (or protection against) chemically induced lung cancer. Hence, human exposure to PAH mixtures with high content of BaP-type hydrocarbons confers a potentially higher health risk than PAH mixtures with low content of procarcinogens.

Animals↗
PubMed2006

[Not Available].

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Journal Article↗
PubMed2005

Carcinogenicity.

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Animal Testing Alternatives↗
PubMed2003

Predictive value of comparative molecular field analysis modelling of naphthalene inhibition of human CYP2A6 and mouse CYP2A5 enzymes.

The objects of this study were first to compare how well the recently constructed structure-inhibition activity relationship models of mouse CYP2A5 and human CYP2A6 predict the interaction of naphthalene in liver microsomes and secondly to study if these CYP enzymes actually oxidize naphthalene. The CoMFA model of CYP2A5 predicted the IC(50) value of naphthalene to be 42 microM (18-115 microM 95% CL) whereas in the in vitro experiment the result was 74 microM (65-83 microM) with the corresponding values for CYP2A6 being 41 microM (18-112 microM) and 25 microM (21-30 microM), respectively. Naphthalene appeared to be a competitive inhibitor both for mouse and human liver microsomal coumarin 7-hydroxylase, which is the specific probe activity for CYP2A5 and CYP2A6. The K(i)-value for the mouse enzyme was between 12-26 microM and for the human enzyme 1.2-5.6 microM. A 1-h in vitro incubation of naphthalene with human and pyrazole treated mouse liver microsomes produced more 1-naphthol than 2-naphthol. Antibody against the purified CYP2A5 inhibited 50-60% of the formation of 1-naphthol and 30-40% of the formation of 2-naphthol. These results indicate that in silico CoMFA models predict relatively well the interaction of naphthalene with CYP2A5 and CYP2A6 and that these CYPs actually oxidize naphthalene in vitro. CoMFA CYP2A5 and CYP2A6 models are thus useful as a technique for elucidating the interaction and potency of untested chemicals with these CYPs.

Animals↗
PubMed2002

Effect of Kupffer cell inactivation on ethanol-induced protein adducts in the liver.

Tissue deposition of protein adducts derived from ethanol metabolism and lipid peroxidation, has been suggested to play a role in the initiation of alcoholic liver disease. The mechanisms modulating adduct formation have, however, remained unclear. We used immunohistochemical methods to examine acetaldehyde (AA) and malondialdehyde (MDA) adducts and cytochrome P4502E1 and P4503A2 expression in rats after administration of (i) an ethanol-diet (n = 6), (ii) ethanol-diet plus gadolinium chloride (GdCl(3)), a selective Kupffer cell toxicant (n = 7), or (iii) control diet (n = 6). A 4 week ethanol treatment resulted in liver steatosis, necrosis, and inflammation and deposition of protein adducts with both AA and MDA, which colocalized with areas of fatty change. The intensities (mean +/- SD) of the immunohistochemical reactions for both AA (2.50 +/- 1.23) and MDA (3.00 +/- 1.10) adducts were significantly higher in the ethanol-fed animals than in the controls (0.083 +/- 0.20) (0.16 +/- 0.25) (p <.001). GdCl(3) prevented adduct accumulation, the mean immunohistochemistry scores being 0.86 +/- 1.07 for AA and 1.64 +/- 0.63 for MDA, the former showing a more striking reduction (p <.01). The hepatic cytochrome enzymes were not different in the ethanol-fed groups with or without GdCl(3). The data indicates that Kupffer cells are involved in the generation of protein adducts with both acetaldehyde and ethanol-induced lipid peroxidation products in alcoholic liver disease.

Acetaldehyde↗
PubMed2002

Lack of association between CYP2A5 induction and apoptosis in mouse primary hepatocytes.

Upregulation of mouse hepatic cytochrome P450 2A5 (CYP2A5) is a process closely associated with hepatocellular damage and formation of liver tumours. 2-Aminopurine, a protein kinase inhibitor modulating cell cycle control, was recently shown to strongly induce CYP2A5 in mouse hepatocytes. The objective of this study was to determine the association between CYP2A5 induction and apoptosis in mouse primary hepatocytes. Five well-characterised CYP2A5 inducers were tested for their ability to affect apoptosis rate, determined by immunohistochemical in situ 3'-end-labelling technique, in a primary mouse hepatocyte model. Transforming growth factor beta (TGFbeta) was used as a positive (proapoptotic) control. Phenobarbital, pyrazole and the mitogen-activated protein kinase inhibitor PD98059 did not significantly affect apoptosis rate in hepatocytes. Norcocaine induced apoptosis at 6 hr (1.8-fold) and 2-aminopurine 12 hr (1.4-fold) after treatment, which is considerably earlier than peaks in the amount of CYP2A5 mRNA. TGFbeta reduced CYP2A5 marker activity, coumarin 7-hydroxylase by 74%. These results indicate that in a primary hepatocyte model (a) there is no systematic correlation between apoptosis and CYP2A5 induction; (b) phenobarbital does not significantly affect the rate of apoptosis; and (c) the induction of apoptosis caused by the chemicals tested occurs considerable earlier than elevation of CYP2A5 expression. Thus, no causal link appears to exist between induction of CYP2A5 and apoptotic rate.

2-Aminopurine↗
PubMed2002

Diabetes and elimination of antipyrine in man: an analysis of 298 patients classified by type of diabetes, age, sex, duration of disease and liver involvement.

UNLABELLED: Effects of diabetes on hepatic drug metabolism in man has not yet been adequately clarified. Two hundred ninety-eight diabetic patients, classified by type of the disease, age, gender, duration of therapy and liver involvement, were investigated. The antipyrine plasma clearance rate and cytochrome P450 content determinations in liver biopsies of subjects with diagnostic liver biopsy were used as indices of hepatic drug metabolising capacity. Drug metabolism was reduced as a function of age. Antipyrine elimination rate was dependent on the type of diabetes (type 1 versus type 2) and gender. Untreated type 1 patients eliminated antipyrine rapidly and insulin treatment normalised antipyrine elimination (clearance rates 89.5 +/- 20.3 versus 58.8 +/- 17.2 ml/min.; P<0.001). Males aged 16-59 years, but not over 60, who responded insufficiently to insulin therapy, had a rapid antipyrine elimination, which could be normalised by readjustment of insulin administration. Women with insufficient glucose control on insulin therapy had antipyrine elimination rate comparable to controls. Among type 2 diabetic patients, women metabolised antipyrine normally, but men over 40 years of age showed a reduced antipyrine metabolism. IN CONCLUSION: Drug metabolism in diabetes is affected by the type of disease, therapy and its effectiveness, and age and gender of the patients. These factors should be taken into account when evaluating overall drug metabolism in diabetic patients. This is especially important when investigating pharmacokinetics of new drugs for diabetic patients at different phases of the disease.

Adolescent↗