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PubMed2006

Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver.

OBJECTIVE: Propofol is commonly used for anesthesia and sedation in intensive care units. Approximately 53% of injected propofol is excreted in the urine as the glucuronide and 38% as hydroxylated metabolites. Liver, kidneys and intestine are suspected as clearance tissues. We investigated the contribution of the liver and kidneys to propofol metabolism in humans using an in vitro-in vivo scale up approach. METHODS: Renal tissue was obtained from five patients who received nephrectomies. Each renal hydroxylation and glucuronidation enzymatic activities in microsomal fractions from patients were performed discretely and their estimation based on the decrease of propofol concentration. Hepatic hydroxylation and glucuronidation activities were also performed separately using human liver microsomes. This estimation is based on the decrease of propofol concentration, assuming that the contribution of hydroxylation activity without NADPH-generating system and glucuronidation activity without UDPGA in each microsomal fraction are negligible. Both renal and hepatic clearances were estimated assuming a well-stirred model. RESULTS: Enzymatic activity of propofol oxidation in renal microsomes was negligible. Although glucuronidation activity in microsomes from kidneys was comparable to that from liver, the hepatic intrinsic clearance predicted from in vitro study was higher than that in kidneys due to the larger tissue volume and higher protein concentration. However, glucuronidation clearance in kidney is relatively similar to that in liver because of blood flow limitation of clearance in both tissues. CONCLUSION: The high degree of hydroxylation activity in liver microsomes is consistent with the blood flow-limited hepatic clearance of propofol. Although the activity of propofol glucuronidation in liver is higher, glucuronidation in kidney may be a substantial contributor.

Aged↗
PubMed2006

A low degree of fatty acid unsaturation leads to high resistance to lipid peroxidation in mitochondria and microsomes of different organs of quail (Coturnix coturnix japonica).

Birds -- particularly long-lived species -- have special adaptations for preventing tissue damage caused by reactive oxygen species. The objective of the present study was to analyse the fatty acid composition and non-enzymatic lipid peroxidation of mitochondria and microsomes obtained from liver, heart and brain of quail (Coturnix coturnix japonica), a short-lived bird. Fatty acids located in total lipids of rat liver, heart and brain mitochondria and microsomes were determined using gas chromatography and lipid peroxidation was evaluated using a chemiluminescence assay. The unsaturated fatty acid content found in mitochondria and microsomes of all tissue examined was approximately 50 and 40%, respectively with a prevalence of C18:1 n9. The C18:2 n6 content in brain mitochondria was significantly lower as compared to liver and heart mitochondria. Whereas the C20:4 n6 content in mitochondria from all tissues examined and brain microsomes was approximately 6%, liver and heart microsomes exhibited lower values. C22:6 n3 was absent in liver mitochondria, very low content in liver microsomes and heart organelles (between 0.5 and 1%) and high content in brain organelles, with mitochondria having the highest value (11%). Whereas liver and heart organelles were not affected when subjected to lipid peroxidation, brain mitochondria were highly affected, as indicated by the increase in chemiluminescence and a considerable decrease of C20:4 n6 and C22:6 n3. These results indicate that a low degree of fatty acid unsaturation in liver and heart organelles of quail, a short-lived bird, may confer advantage by decreasing their sensitivity to lipid peroxidation process.

Animals↗
PubMed1985

Catalytic activity and substrate specificity of the flavin-containing monooxygenase in microsomal systems: characterization of the hepatic, pulmonary and renal enzymes of the mouse, rabbit, and rat.

Inhibitory antibodies against NADPH-cytochrome P-450 reductase, detergent solubilization to dissociate functional interaction between the reductase and cytochrome P-450, and selective trypsin degradation have been used to characterize flavin-containing monooxygenase activity in microsomes from different tissues and species. A comparison of assay methods is reported. The native microsome-bound flavin-containing monooxygenase of mouse, rabbit, and rat liver, lung, and kidney can metabolize compounds containing thiol, sulfide, thioamide, secondary and tertiary amine, hydrazine, and phosphine substituents. Therefore, this enzyme from these common experimental animals has catalytic capabilities similar to those of the well-characterized porcine liver enzyme. True allosteric activation by n-octylamine does not appear to be a property of either the mouse, rabbit, or rat liver enzymes, but is a property of the pig liver and mouse lung enzymes. The microsomal pulmonary flavin-containing monooxygenase of the rabbit has some unique substrate preferences which differ from the mouse lung enzyme. Both the rabbit and mouse pulmonary enzymes have recently been shown to be distinct enzyme forms. However, the rat pulmonary flavin-containing monooxygenase appears to be catalytically identical to the rat liver enzyme, and does not have any of the unusual catalytic properties of either the rabbit or mouse lung enzymes. Enzyme activity of mouse, rabbit, and rat kidney microsomes is qualitatively similar to the hepatic activities. Substrates which saturate the microsome-bound flavin-containing monooxygenase at 1.0 mM, including thiourea, thioacetamide, methimazole, cysteamine, and thiobenzamide, are metabolized at common maximal velocities. This suggests that the kinetic mechanism of the native enzyme is similar to that established for the isolated porcine liver enzyme in that the rate-limiting step of catalysis occurs after substrate binding, and that all substrates capable of saturating the microsomal enzyme should be metabolized at a common maximal velocity.

Animals↗
PubMed1984

Arachidoyl- and arachidonoyl-CoA elongation mechanism in swine cerebral microsomes.

Long-chain saturated and polyunsaturated fatty acyl-CoA elongations were studied in swine cerebral microsomes. The elongation of endogenous palmitoyl-CoA to stearate was highly active in both cerebral and liver microsomes, whereas those of arachidoyl-CoA (20:0-CoA) and endogenous arachidonoyl-CoA (20:4-CoA) were high in cerebral microsomes, but negligible in liver microsomes. The elongation of 22:4 to 24:4 was also observed in cerebral microsomes. Both NADPH and NADH at 500 microM were effective in elongation of 16:0-, 20:0- and 20:4-CoA, whereas NADPH was more effective in elongation of 22:4 to 24:4 than NADH. The incorporation of deuterium atoms to the elongated product was detected by the technique of mass fragmentography when the NADPH-dependent elongations of 20:0-CoA and 20:4-CoA were performed in 2H2O medium upon cerebral microsomes. The number of incorporated deuterium atoms into 22:0 elongated from 20:0-CoA was mainly two, and that into 22:4 elongated from 20:4-CoA was mainly three. These results indicated that part of hydrogens in elongated arachidoyl- and arachidonoyl-CoA were transferred from NADPH.

Acyl Coenzyme A↗
PubMed1988

Participation of microsomal aldehyde reductase in long-chain fatty alcohol synthesis in the rat brain.

The participation of microsomal aldehyde reductase in long-chain fatty alcohol synthesis in the rat brain was examined. A reaction mixture of [1-14C]hexadecanoic acid with brain microsomes and NADPH formed two radioactive products having the same mobilities as pure hexadecanal (RF 0.61) and hexadecanol (RF 0.22), respectively, on TLC plates. The product of the RF 0.61 spot was further identified as hexadecanal using gas-liquid chromatography after methylation and TLC of its reduced product with LiAlH4 and semicarbazide. The ratio of hexadecanal to hexadecanol varied from 0.4 to 1.2 under the present experimental conditions. When solubilized rat brain microsomes were applied to a Sepharose 4B column coupled with the rabbit antibody raised against rat liver microsomal NADPH-cytochrome-c reductase, which reacts with aldehyde reductase from rat brain, the eluted fraction ceased to form [14C]hexadecanol but continued to form [14C]hexadecanal from [14C]hexadecanoic acid. These results strongly indicate that hexadecanal is the intermediate in the synthesis of hexadecanol from hexadecanoic acid in rat brain microsomes with the participation of microsomal aldehyde reductase.

Alcohol Oxidoreductases↗
PubMed1992

Differential oxidase activity of hepatic and pulmonary microsomal cytochrome P-450 isozymes after treatment with cytochrome P-450 inducers.

Phenobarbital, 3-methylcholanthrene, acetone and pyrazole were used as inducers of cytochrome P450 and the NADPH-dependent oxidase activity (O-2 production) of pulmonary and hepatic microsomes was determined. Oxidase activity of microsomes from 3-methylcholanthrene-treated rats was significantly decreased as compared to that of controls when expressed on the basis of cytochrome P450 content (30% decrease for liver, 60% decrease for lung). The oxidase activity of liver microsomes from pyrazole-treated rats showed a significant increase, whereas phenobarbital treated microsomes had average superoxide-generating activity. The contribution of cytochromes CYP 1A, CYP 2B and CYP 2E1 to superoxide-generating activity was investigated using monoclonal antibodies. Monoclonal antibody 1-91-3 against CYP 2E1 inhibited superoxide generation by 58% in liver microsomes from pyrazole-treated rats. Monoclonal antibodies 1-7-1 and 2-66-3 against CYP 1A and CYP2B, respectively, had no effect on superoxide generation. These results indicate that different cytochrome P450 isoforms are mainly responsible for differential superoxide generating activities of microsomes and complement the reconstitution study of Morehouse and Aust. Furthermore, our study indicates that CYP 1A1, induced by 3-MC, demonstrates an unusually low oxidase activity.

Animals↗
PubMed1983

Biotransformation of benzo[a]pyrene and 7-ethoxyresorufin and heme-staining proteins in microsomes from human fetal liver and placenta.

Microsomal proteins from human fetal livers and mid-gestational and term placentas were stained for heme in an attempt to detect multiple forms of cytochrome P-450. In fetal liver microsomes five protein bands staining for heme in the mol. wt region 46,000-60,000 were found. In the placentas two bands were seen in the region 46,000-52,000. Fetal liver and placental microsomes were assayed for metabolism of benzo[a]pyrene (B[a]P and 7-ethoxyresorufin (7-EOR). The B[a]P metabolites were separated using high performance liquid chromatography. Following incubations with fetal liver microsomes, in general only phenols were detectable, while after incubations with mid-gestational as well as term placentas from smoking women, the 9,10-, 4,5- and 7,8-dihydrodiols were also formed. No quinones were detected. Placental microsomes from non-smoking women did not catalyse the formation of B[a]P metabolites. The 7-EOR O-de-ethylase activity was in the same range (2-5 pmol/min x mg microsomal protein) in the fetal livers as in the mid-gestational placentas. The activities were somewhat higher in the placentas originating from smokers. No correlation between enzymatic activities in vitro and intensity of any specific protein band was observed for the fetal livers of placentas studied.

Benzo(a)pyrene↗
PubMed1983

Oxidation of thiobenzamide by the FAD-containing and cytochrome P-450-dependent monooxygenases of liver and lung microsomes.

Two distinct microsomal pathways involved in the metabolism of thiobenzamide to thiobenzamide S-oxide have been identified and quantitated in the liver and lungs of mice and rats, using a highly inhibitory antibody against NADPH-cytochrome P-450 reductase. Approximately 50 and 65% of the oxidation in mouse and rat liver microsomes, respectively, was due to the FAD-containing monooxygenase, the remainder being catalyzed by cytochrome P-450. In the mouse lung, S-oxidation was predominantly via the FAD-containing monooxygenase while that in the rat lung was about 60% via the FAD-containing enzyme and 40% via cytochrome P-450. Cytochrome P-450-dependent S-oxidation of thiobenzamide was induced in the liver by treatment of mice with phenobarbital and slightly increased by treatment with 3-methylcholanthrene, while in rat liver either of these treatments caused only a small increase in metabolism due to cytochrome P-450. Thermal inactivation of the FAD-containing monooxygenase left the cytochrome P-450 component essentially unchanged. Thermally treated microsomes had a pH activity profile characteristic of cytochrome P-450 and were less inhibited by methimazole and thiourea when compared to untreated microsomes. Female mouse liver microsomes had a much higher, and female rat liver microsomes a lower, ability to S-oxidize thiobenzamide when compared to the males.

Amides↗
PubMed1986

Sex differences in cytochrome P-450 isozyme composition and activity in kidney microsomes of mature rainbow trout.

Kidney microsomes from sexually mature male, as opposed to female, rainbow trout displayed an approximately 20-fold higher cytochrome P-450 specific content, NADPH-cytochrome c reductase activity, and rates of hydroxylation of lauric acid, testosterone, progesterone and aflatoxin B1. Little or no sex difference in metabolism was observed with benzo[a]pyrene or benzphetamine as substrates. A similar pattern was observed in hepatic microsomes from these fish, but the difference was much less striking (approximately 2-fold higher activity in males). Juvenile trout (both sexes) possessed activities intermediate between mature males and females. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of kidney and liver microsomes of juvenile and sexually mature male and female trout suggested that the striking sex difference in kidney could be due to the high amount of trout P-450 isozyme LM2 in sexually mature males. Immunoquantitation of LM2, performed by Western Blotting and immunostaining with rabbit anti-trout LM2-IgG, confirmed that mature male kidney contained much higher levels of P-450 LM2 than juvenile or female kidney, or even of liver microsomes of all three groups. The amount of P-450 LM2 in mature female kidney microsomes was barely detectable. The high amount of LM2 in male trout kidney is consistent with the high activity of these microsomes towards lauric acid and aflatoxin B1, which have been shown previously to be preferentially metabolized by trout P-450 LM2. It is suggested that rainbow trout may serve as an alternative to the rat as an animal model for the study of sex-dependent differences in cytochromes P-450.

Animals↗
PubMed1995

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human placental microsomes.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) can be activated metabolically by cytochrome(s) P450 to DNA-damaging agents that result in the formation of tumors in various organs of several animal models. In the present study, 30-min incubations at 37 degrees containing 5 mg/mL pooled human placental microsomes, 36 nmol NNK (including 2 microCi [5-3H]NNK) and a 5 mM concentration of either NADH, NADPH, or both cofactors together resulted in the formation of 11.43 +/- 0.32, 35.40 +/- 4.64, and 44.05 +/- 1.66 pmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)/mg protein/min (mean +/- SD, N = 3), respectively. Similar experiments using 7, 9, and 11 mM NADH, NADPH, and both cofactors together in equimolar concentrations yielded results that suggest that NADH- and NADPH-dependent reductions of NNK are catalyzed by different enzymes. Computer simulations for the production of NNAL based on various kinetic models corroborated the conclusion drawn from the empirically derived data. In human placental microsomes, the Km,app and Vmax,app for the formation of NNAL were 1021.9 +/- 251.5 microM and 4360.7 +/- 991.7 pmol/mg protein/min, respectively. Inhibition of cytochrome P450-dependent activities by carbon monoxide and dicumarol (100 and 200 microM) resulted in an average increase of NNAL production of 40 and 56%, respectively, suggesting that P450-dependent biotransformation of NNK is occurring in the absence of inhibitors. Similarly, polyclonal goat IgG against rabbit P450 reductase resulted in a 12% increase in the production of NNAL when compared with control values. Thirty micromolar rutin, ethacrynic acid, cibacron blue 3GA, and iodoacetic acid, known inhibitors of certain human carbonyl reductase(s), incubated with placental microsomes containing an equimolar concentration of NNK, did not have a significant effect on the production of NNAL. These results establish that: (1) cytochromes P450 are likely involved in the metabolism of NNK by human placental microsomes, (2) metabolism of NNK to NNAL by human placental microsomes is catalyzed by an NADPH-dependent carbonyl reductase(s) and an NADH-dependent carbonyl reductase(s), and (3) reduction of NNK to NNAL is catalyzed by a placental microsomal carbonyl reductase(s) not previously described.

Alcohol Oxidoreductases↗
PubMed1975

Non-enzymatic and microsome-dependent binding of poly-cyclic hydrocarbons to DNA and polynucleotides.

The binding of tritium-labeled 7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (BP) and 3-methylcholanthrene (MCA) to DNA or polynucleotides in vitro was re-examined both in the presence and in the absence of rat liver or human placental microsomes. A high level of non-enzymatic binding was evident when thymus DNA was used as acceptor. This non-enzymatic binding made it difficult to determine the effect of microsomes, except in the case of BP when induced rat microsomes were used. Better results were obtained using polynucleotides: a definite microsome-dependent binding occurred between all the polynucleotides and all the hydrocarbons tested. No clear evidence of binding catalysed by microsomes from human placenta was found except in polynucleotide-BP interactions: further studies are required to completely evaluate the ability of such nucleic acid-microsomal system for testing in vitro possible oncogenic substances in animals and humans.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Liver, kidney and small-intestine microsomal-mediated mutagenicity of carcinogenic aromatic amines.

The mutagenicity of 2-aminofluorene, 4-aminobiphenyl and 3,2'-dimethylaminobiphenyl towards Salmonella typhimurium was studied in the presence of microsomes from liver, kidney and small intestine of untreated and pretreated rats. The aim was to study a possible correlation between the organotropism of these amines and their activation into mutagenic intermediates by these three tissues. Pretreatment of the rats with phenobarbital, Aroclor 1254 and 3-methylcholanthrene injected intraperitoneally increased the liver microsomal-mediated mutagenic activity of the three amines but remained without effect on the activating capacity of microsomes from the kidney and small intestine. However, pretreatment with 3-methylcholanthrene administered intragastrically increased the small-intestine microsomal-mediated mutagenicity of 2-aminofluorene almost 3-fold but remained without effect on the mutagenicity of 4-aminobiphenyl and 3,2'-dimethylaminobiphenyl. No mutagenic effect was observed with 4-aminobiphenyl in the presence of kidney microsomes or with 4-aminobiphenyl and 3,2'-dimethylaminobiphenyl in the presence of small-intestine microsomes, obtained from either untreated or pretreated animals. It is concluded that no relationship exists between the mutagenic activities of the three amines, as detected in the Ames test, and their carcinogenic organotropisms.

Aminobiphenyl Compounds↗
PubMed1984

Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice.

In vitro studies with male ICR mouse renal cortical slices have indicated that chloroform (CHCl3) is metabolized by the kidney to a nephrotoxic intermediate, possibly by a cytochrome P-450-dependent mechanism similar to that occurring in the liver. In this investigation, metabolism of 14CHCl3 by microsomes prepared from renal cortex and liver provided definitive evidence for a role of cytochrome P-450 in the renal metabolism and toxicity of CHCl3. 14CHCl3 was metabolized to 14CO2 and covalently bound radioactivity by male renal cortical microsomes; metabolism required oxygen, a NADPH regenerating system, was dependent on incubation time, microsomal protein concentration, and substrate concentration, and was inhibited by carbon monoxide. Consistent with the absence of CHCl3 nephrotoxicity in female mice, little or no metabolism of 14CHCl3 by female renal cortical microsomes was detected. CHCl3 produced a type I binding spectrum with oxidized male renal cortical and hepatic microsomes. Incubation of glutathione with microsomes and 14CHCl3 increased the amount of aqueous soluble metabolites detected with a concomitant decrease of metabolism to 14CO2 and covalently bound radioactivity, suggesting the formation of a phosgene conjugate as has been described for hepatic CHCl3 metabolism. These data support the hypothesis that renal cytochrome P-450 metabolizes CHCl3 to a nephrotoxic intermediate.

Animals↗
PubMed1995

Comparison of rat hepatic and pulmonary microsomal metabolism of benzene and the lack of benzene-induced pneumotoxicity and hepatotoxicity.

Since little is known about the toxicity of benzene in the lung or if the lung is capable of metabolizing benzene, the ability of the lung to bioactivate or detoxify benzene and the pneumotoxicity of benzene were determined. While overall metabolism was lower, pulmonary microsomes converted benzene (17.5 microM) to hydroquinone, considered to be a marker for benzene toxicity, in proportionately greater amounts than did hepatic microsomes. Treatment of rats with pyridine, an inducer of CYP2E1, enhanced hepatic microsomal metabolism of benzene, although benzene, which is also considered to be an inducer of CYP2E1, did not. Neither pyridine nor benzene treatment induced the pulmonary microsomal metabolism of benzene. When hepatic and pulmonary microsomes from control and pyridine-treated rats were incubated with benzene (17.5 microM) and the CYP2E1 inhibitor, diethyldithiocarbamate, benzene metabolism was significantly inhibited, indicating that CYP2E1 is the predominant cytochrome P-450 isozyme involved in hepatic and pulmonary metabolism in microsomes from control and pyridine-treated rats. Benzene (600 mg/kg body weight, i.p.) did not cause significant lung cell damage as determined by measurement of gamma-glutamyltransferase and lactate dehydrogenase in bronchoalveolar lavage fluid. Induction of CYP2E1 and CYP2B1/2 with pyridine and phenobarbital, respectively, did not alter this lack of effect. Thus, the primary concern about benzene and the lung should focus on benzene metabolism as opposed to acute toxicity.

Animals↗
PubMed1983

The metabolism of 3-methylcholanthrene by liver and lung microsomes: effect of enzyme inducing agents.

The metabolism of 3-methylcholanthrene (3-MC) by rat liver and lung microsomes was investigated. The animals were pretreated with various inducing agents to determine the effect which microsomal induction has on metabolic profile. Metabolites were separated by high pressure liquid chromatography. Major metabolism was associated with three peaks: 2-hydroxy-3-MC, 1-hydroxy-3-MC and a peak that co-chromatographs with 3-MC 11,12-oxide and probably contains phenols. Pretreatment of animals with various inducing agents caused an increase in total metabolism as well as in specific metabolites. However, lung microsomes from phenobarbital treated animals were less efficient at metabolizing 3-MC than control microsomes. Liver and lung microsomes converted 3-MC to qualitatively similar products. No metabolites were formed by lung microsomes that were not also formed by those from liver.

Animals↗
PubMed1989

In vitro formation of organ-specific ultimate carcinogens of 4-dimethylaminoazobenzene and urethan by microsomes.

In order to determine the organ-specific carcinogenicity of 4-dimethylaminoazobenzene (4-DAB) and urethan, their metabolites formed in vitro by incubation with the microsomes from liver, lungs, brain and kidneys of rats were isolated by thin-layer chromatography. 4-DAB was found to be metabolized to give two major products, 4-aminoazobenzene and N-hydroxy-4-aminoazobenzene, only when incubated with liver microsomes. These metabolites were not detected when microsomal suspensions of lungs, brain and kidneys were used. Similarly, urethan was found to yield three metabolites, N-hydroxy derivative of ethyl carbamate, N-hydroxyvinyl carbamate, and epoxy derivative of ethyl carbamate, on incubation with lung microsomes, but not with the microsomes from liver, brain and kidneys. As the potential carcinogenic moieties were only formed by incubating these two compounds with the microsomes of their target organs, their organ-specific carcinogenicity may be explained.

Animals↗
PubMed1989

Cytochrome P-450-dependent metabolism of xenobiotics. A comparative study of rat hepatic and plant microsomal metabolism.

1. A comparison was made between rat hepatic and plant microsomal cytochrome P-450 and cytochrome P-450 linked enzymic activities. 2. The results show that, compared with plant microsomes, rat hepatic microsomal protein concentrations were 165-fold higher, and rat hepatic cytochrome P-450 concentration were 32-fold higher. 3. Rat hepatic Cytochrome P-450 linked enzyme activities were 1765-fold and 25-fold greater when compared with plant microsomes using aldrin and biphenyl as substrates, respectively. 4. Rats metabolised biphenyl to 2- and 4-hydroxybiphenyl, whereas plants produced only the latter metabolite. 5. Pretreatment of rats and plant tissues with biphenyl, Aroclor 1248 and the sodium salt of phenobarbital increased significantly the microsomal protein concentrations, and enzyme activities linked to cytochrome P-450. 6. Unlike rat microsomes, those of plants were unable to metabolise halosubstituted biphenyls at measurable rates.

Aldrin↗
PubMed1998

Effects of pycnogenol on the microsomal metabolism of the tobacco-specific nitrosamine NNK as a function of age.

NNK is a potent environmental carcinogen to which smokers and non-smokers are exposed. The response to NNK can be altered by various factors including nutrition. In this study, we examined the effects of pycnogenol on the in vitro metabolism of the tobacco-specific nitrosamine NNK by liver and lung microsomes from 6- and 20-month-old male F344 rats. The major NNK metabolic pathway in liver microsomes was carbonyl reduction, while alpha-hydroxylation was the major pathway in lung microsomes irrespective of age. Pycnogenol (40 and 120 microg/ml) exhibited a statistically significant inhibition of carbonyl reduction and alpha-hydroxylation pathways in liver microsomes from both age groups and in addition to these pathways, pycnogenol inhibited the N-oxidation pathway in lung microsomes. The liver and lung microsomes from 20-month-old rats were less active than from 6-month-old rats although the difference was not statistically significant.

Aging↗