Pulmonary Metabolism Research Articles

The effects of sepsis on intestinal and pulmonary glutamine metabolism

The effects of sepsis on intestinal and pulmonary glutamine metabolism

Localization of pulmonary carbonyl reductase in guinea pig and mouse: enzyme histochemical and immunohistochemical studies.

We studied the localization of carbonyl reductase (E.C. 1.1.1.184) in guinea pig and mouse lung by enzyme histochemistry and immunohistochemistry, using antibodies against the guinea pig lung enzyme which crossreacted with the lung enzymes of both animals. Carbonyl reductase activity was detectable in the bronchiolar epithelial cells of small airways and in alveolar cells. In the immunohistochemical staining for carbonyl reductase, the reaction was strongest in the non-ciliated bronchiolar cells (Clara cells) and was weak in the ciliated cells and type II alveolar pneumocytes. Injection of a single dose of naphthalene led to significant impairment of carbonyl reductase activity and of microsomal mixed-function oxidase activities in mouse lung, with a marked decrease in both activity and immunoreactive staining in the bronchiolar epithelial cells. The results indicate that carbonyl reductase is localized primarily in the Clara cells, which are known to be sites of pulmonary drug metabolism.

Age-Dependent Effect of Ozone on Pulmonary Eicosanoid Metabolism in Rabbits and Rats

Age-Dependent Effect of Ozone on Pulmonary Eicosanoid Metabolism in Rabbits and Rats. GUNNISON, A. F., FINKELSTEIN, I., WEIDEMAN, P., SU, W.-Y., SOBO, M., AND SCHLESINGER, R. B. (1990). Fundam. Appl Toxicol. 15, 779–790. Acute exposures to ozone have previously been shown to cause quantitative changes in the spectrum of arachidonic acid (AA) metabolites in lung lavage fluid. Since age appears to be an important variable in the toxicity of inhaled ozone, we investigated its effect on ozone-induced changes in pulmonary eicosanoid metabolism. Rats and rabbits ranging in age from neonates to young adults were exposed either to air or to 1 ppm ozone for 2 hr. Lung lavage fluid was collected within 1 hr following exposure and analyzed for its content of selected eicosanoids. In both species, there was a pronounced effect of age on ozone-induced pulmonary eicosanoid metabolism. Ozone-exposed animals at the youngest ages examined had severalfold greater amounts of two products of the cyclooxygenase pathway, prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a), than did age-matched controls. This effect lessened and eventually disappeared as the animals grew toward adulthood. In rabbits, ozone also induced increases in 6-keto-prostaglandin F1a and thromboxane B2, but these changes were of lesser magnitude and evident only in the youngest rabbits exposed. There was no observed effect of ozone on lung lavage content of leukothriene B4. Indices of nonspecific pulmonary damage, i.e., protein concentration in lung lavage fluid and total number and viability of lavaged lung cells, were affected by ozone exposure, but not in an age-dependent manner that correlated with changes in pulmonary eicosanoid metabolism. In vitro ozone exposure of lung macrophages from naive rabbits of the same age range as those exposed in vivo demonstrated that ozone is capable of stimulating the elaboration of PGF2a and especially PGE2. However, the increase in lavage fluid PGE2 and PGF2a caused by ozone inhalation could not be attributed to macrophage metabolism conclusively since elaboration of PGE2 and PGF2a by cultured macrophages was not enhanced by prior in vivo ozone exposure. In an ancillary study it was shown that 15-hydroxyprostaglandin dehydrogenase (PGDH) activity in rabbit lung homogenates was not affected by prior exposure to ozone, indicating that the increase in lung lavage fluid eicosanoids that occurred in these animals could not be explained by inhibition of PGDH.

Pulmonary extraction and metabolism of leukocytes, amines and labeled colloids

Pulmonary extraction and metabolism of leukocytes, amines and labeled colloids

Pulmonary clearance of atrial natriuretic peptides

Pulmonary clearance and metabolism of atrial natriuretic peptides were studied in isolated perfused rat lungs utilizing high performance liquid chromatography and radioimmunoassay analyses. The disappearance rate of atrial peptides from the perfusion medium followed pseudo-first order kinetics and was associated with formation of lower molecular weight products. Pretreatment of the lungs with MK-521, an angiotensin converting enzyme inhibitor, decreased pulmonary clearance values for both atrial natriuretic peptide and atriopeptin III but did not affect clearance of atriopeptin II. Aminopeptidase inhibition also decreased the rate of atrial natriuretic peptide clearance, however carboxypeptidase inhibition did not affect atrial natriuretic peptide, atriopeptin III or atriopeptin II clearance. The results suggest that the lung through uptake and metabolic processes participates in the clearance and enzymatic metabolism of the atrial natriuretic peptides.

Modulation of Pulmonary Eicosanoid Metabolism following Exposure to Sulfuric Acid

Modulation of Pulmonary Eicosanoid Metabolism following Exposure to Sulfuric Acid

Physiologically Based Pharmacokinetic Model of the Metabolism of Trichloroethylene by an Isolated Ventilated Perfused Lung

AbstractBiotransformation is often a determinant of pharmacokinetic behavior and toxicity. While the liver is usually the quantitatively most significant site, metabolism in other tissues may cause nonhepatic toxicity and also may affect the pharmacokinetic behavior of chemicals. In these cases, structural models of pharmacokinetic and pharmaco-dynamic processes can explicitly describe the nonhepatic metabolism. As a first step in development of such models for a series of volatile halogenated toxicants, a “physiologically realistic” isolated, ventilated perfused lung (IVPL) was used to quantify the pulmonary metabolism of trichloroethylene (TCE). Concurrent with laboratory studies, a mathematical, structurally based model of the IVPL was developed and used in computer simulations. These simulations were used for refinement of the IVPL design, estimation of pulmonary Vmax and Km for TCE from metabolite data, and estimation of pulmonary first-pass metabolic clearance. The Vmax and Km estimates were obtaine...

Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion.

Glutathione is a tripeptide important in a number of diverse cellular functions including enzymatic reactions involved in prostaglandin endoperoxide metabolism. We have previously reported that cyclophosphamide administration to rats results in acute lung injury manifested by increased bronchoalveolar lavage albumin concentrations. In the current study we examine whether cyclophosphamide treatment affects pulmonary glutathione stores or bronchoalveolar endoperoxide metabolic product levels and whether these effects may be related to acute lung injury caused by the drug. We show that cyclophosphamide treatment causes a dose-dependent reduction in pulmonary glutathione stores 4 h after drug administration. In addition, acute lung injury as the result of cyclophosphamide can be abrogated by coadministration of oxothiazolidine carboxylate, an intracellular cysteine delivery system that also reverses pulmonary glutathione depletion induced by cyclophosphamide in our study. Finally, cyclophosphamide treatment reduces prostaglandin E2 concentrations in bronchoalveolar lavage and alveolar macrophage culture supernatant in a dose-dependent fashion and increases bronchoalveolar thromboxane concentrations in low dose-treated animals. These effects are reversed to a variable degree by coadministration of oxothiazolidine carboxylate. Our study suggests in vivo pulmonary arachidonic acid metabolism and cyclophosphamide-induced acute lung injury are modulated by cellular glutathione stores. These findings may have important implications for the treatment of acute lung injury.

Role of PGF 2α in the superior mesenteric artery-induced shock

The role of PGF 2α in circulatory shock of intestinal origin was investigated in anesthetized dogs by measuring PGF 2α levels in superior mesenteric vein, right ventricle, aorta, and femoral vein during superior mesenteric artery occlusion-induced shock by comparing the circulatory effects of exogenous PGF 2α injected into either the superior mesenteric or the femoral vein and by inhibiting of prostanoid synthesis with indomethacin. Release of the superior mesenteric artery occlusion caused a dramatic decrease in mean arterial blood pressure; an increase in mean portal venous pressure, and more than fivefold increases in plasma PGF 2α levels in superior mesenteric vein, right ventricle, and aorta. In spite of the decreased mean arterial blood pressure, postocclusion blood flow in the mesenteric artery did not fall below preocclusion values. Indomethacin in itself, significantly reduced plasma PGF 2α levels as well as intestinal blood flow and increased mean arterial blood pressure in animals without superior mesenteric artery occlusion. Furthermore, indomethacin attenuated the magnitude of postocclusion hypotension and completely prevented PGF 2α production during superior mesenteric artery occlusion shock. Exogenous PGF 2α 10 μg/kg injected into the superior mesenteric or femoral vein produced hypotension or hypertension, respectively. When PGF 2α was injected into the superior mesenteric vein, the plasma level of PGF 2α in the aorta was similar to that observed during superior mesenteric artery occlusion shock, whereas PGF 2α injected into the femoral vein gave a significantly higher concentration. Pulmonary metabolism of PGF 2α was significantly reduced in shock. The present results suggest that PGF 2α released by intestinal tissues might play an important role in shock caused by intestinal ischemia.

Carcinogen Metabolism Studies in Human Bronchial and Lung Parenchymal Tissues

The pulmonary metabolism of xenobiotics was investigated by measuring the glutathione content and the activity of the aryl hydrocarbon hydroxylase, epoxide hydrolase, glutathione S-transferase, and uridine 5' -diphosphoglucuronosyl transferase enzymes in S-12 fractions of bronchial tree and peripheral lung parenchyma obtained at surgery from 21 patients. In parallel, the same preparations were used to assess either the activation of promutagens, i.e., benzo(a)pyrene, 2-aminofluorene, cyclophosphamide, and a cigarette smoke condensate, to metabolites reverting his- Salmonella typhymurium strains, or the decrease of direct-acting mutagens, i.e., sodium dichromate, 4-nitroquinoline N-oxide, epichlorohydrin, and ICR 191. As compared to bronchus preparations, parenchymal preparations contained considerably higher concentrations of reduced glutathione, had a significantly higher epoxide hydrolase activity, and, as assessed by means of a quantitative index, were more efficient in activating 2-aminofluorene and in reducing the mutagenicity of dichromate and 4-nitroquinoline N-oxide. These data may suggest that parenchymal lung tissue is more capable than bronchial tissue to detoxify reactive intermediates of xenobiotics, possibly explaining the greater susceptibility of bronchi to cigarette smoke-induced cancers.

Effect of pH on pulmonary vascular tone, reactivity, and arachidonate metabolism

We studied the effects of perfusate pH on pulmonary vascular tone, reactivity, and thromboxane and prostacyclin synthesis in isolated buffer-perfused rabbit lungs. Extracellular acidosis did not affect base-line vascular tone, but alkalosis had a biphasic effect. Increasing the perfusate pH from 7.40 to 7.65 caused vasodilation, whereas raising pH to 7.70-8.10 caused vasoconstriction. Removing calcium (Ca2+) from the perfusate completely prevented the vasoconstriction caused by alkalosis. Perfusate pH strikingly affected pulmonary vascular reactivity. Acidosis inhibited the vasoconstriction caused by thromboxane and potassium chloride (KCl) but did not affect the response to angiotensin II. Alkalosis, in contrast, augmented the vasoconstriction caused by thromboxane and angiotensin II but reduced the vasoconstriction caused by KCl. Changes in pH also altered thromboxane and prostacyclin synthesis after the infusion of exogenous arachidonic acid (AA) or the endogenous release of AA by the lipid peroxide tert-butyl hydroperoxide.

Prostaglandin E 1 attenuates postischemic contractile dysfunction after brief coronary occlusion and reperfusion

We have previously demonstrated that administration of the prostacyclin analogue iloprost improved postischemic functional recovery in reversibly injured ischemic-reperfused myocardium. The present study investigated the effects of administering an endogenous vasodilator prostanoid, prostaglandin E 1 (PGE 1), in the stunned myocardium (15 minutes of coronary artery occlusion and 3 hours of reperfusion) of anesthetized dogs. The percentage of regional myocardial segment shortening (%SS) after administration of PGE 1 by two routes, intravenously (1 μg/kg/min) or intraatrially (0.1 μg/kg/min), to avoid pulmonary metabolism, 15 minutes before and throughout the period of occlusion, was compared to %SS in a control group treated with saline solution. Nearly equivalent reductions in mean arterial pressure during occlusion compared to pretreatment control (PTC) values were produced by intravenous (33%) or intraatrial (25%) PGE 1. There was no difference in transmural myocardial blood flow (radioactive microsphere technique) in the ischemic region between the PGE 1-treated and control groups at any time. Although there were no differences in %SS in the nonischemic region between groups throughout the experiment, postischemic recovery of segment function in the ischemic-reperfused area was significantly improved ( p < 0.05) at all times during reperfusion by intravenous PGE 1 (%SS of PTC: 30 minutes = 65 ± 8; 3 hours = 58 ± 7) or intraatrial PGE 1 (%SS of PTC: 30 minutes = 57 ± 12; 3 hours = 50 ± 4) compared to the control group (%SS of PTC: 30 minutes = 25 ± 13; 3 hours = 10 ± 13). Thus treatment with PGE 1 attenuates postischemic contractile dysfunction in the stunned myocardium. The mechanism by which PGE 1 produces these salutary actions is unknown, but it may be partially related to a reduction in afterload during occlusion or by one or more prostaglandin-mediated beneficial effects, such as inhibition of neutrophil function, a cytoprotective action at cellular membranes, or both.

Detection of leukotrienes B4, C4 and of their isomers in arterial, mixed venous blood and bronchoalveolar lavage fluid from ARDS patients

Seven patients with the adult respiratory distress syndrome (ARDS) were studied. As a control group we used 6 surgical patients who underwent minor surgical operation (inguinal hernia). For both groups the same sample collection and analysis was used. The presence of leuktorienes (LTs) B4 and C4 and of their isomers 11-trans LTC4 and delta 6-trans-12-epi LTB4 was determined in arterial, mixed venous blood and in bronchoalveolar lavage (BAL) fluid. The samples, analysed by reverse phase high performance liquid chromatography (RP-HPLC), showed a similar chromatographic picture among ARDS patients, while the control group showed no detectable amounts of LTs in BAL or blood. The distribution of these arachidonic acid metabolites in mixed venous blood, arterial blood and BAL seems to suggest pulmonary metabolism and/or inactivation. It is suggested that these mediators act as humoral factors in pathogenesis of the ARDS.

Role of prostanoids in respiratory failure during circulatory shock of intestinal origin in dogs

The role of prostanoids in respiratory failure during circulatory shock of intestinal origin was investigated in anesthetized, non-ventilated dogs by measuring PGF 2α thromboxane B 2 (TXB 2) and 6-keto prostaglandin F 1α (PGF 1α) in arterial and mixed venous (right ventricle) blood samples during superior mesenteric artery occlusion-induced (SMAO) shock. Release of the SMAO caused a dramatic decrease in mean artrial blood pressure (MABP), arterial and mixed venous pO 2, hyperventilation and a more than 2 fold increase in levels of prostanoid studied within 5 min. At the same time, arterial and mixed venous pCO 2 and pH remained unchanged. Thereafter, 6-keto PGF 1α concentration decreased so that at 60 min post release it was not significantly different from that of control values. PGF 2α and TXB 2 levels rose continously during shock. Respiratory failure which occured after declamping was characterized by low pO 2 and oxygen saturation and hyperventilation throughout the experiment. Pulmonary metabolism of PGF 2α was significantly reduced in shock. Indomethacin significantly attenuated the magnitude of postocclusion hypotension and respiratory failure, furthermore reduced prostanoid production. The present results suggest that PGF 2α and thromboxane A 2 released by intestinal tissues might play an important role in the development of respiratory failure in shock caused by intestinal ischemia.

Kinetics of pulmonary surfactant phosphatidylcholine metabolism in the lungs of silica-treated rats

Exposure of rats to silica by intratracheal injection increased the intra- and extracellular compartments of pulmonary surfactant phospholipid. These changes were dose and time dependent, but both pools were not affected equally. Seven days after the instillation of 10 mg of silica, the intracellular pool increased 13.3-fold, from 1.49 ± 0.30 to 19.86 ± 0.77 mg of surfactant phospholipid per pair of lungs, and the extracellular pool increased 7.4-fold, from 1.87 ± 0.79 to 13.79 ± 0.72 mg of surfactant phospholipid per pair of lungs. To investigate the physiologic processes responsible for these massive accumulations of surfactant, [ 14C]choline was injected into the tail veins of control and silica-treated rats and the specific activity of surfactant phospholipids within the intracellular and extracellular pools was determined at various times between 0 and 26 hr after injection. All of the processes measured were increased in response to silica exposure, but not to the same extent. At 1 hr, incorporation of [ 14C]choline into the intracellular surfactant pool was increased 12.6-fold above controls, from 4.8 ± 1.1 × 10 3 to 60.6 ± 26.6 × 10 3 dpm. The flux of [ 14C]choline-labeled phospholipid from the intracellular to the extracellular pool was increased 7.3-fold, from 102 ± 10 to 749 ± 39 μg/hr in silica-treated animals, but its disappearence from the extracellular pool was increased only 5.0-fold, from 87 ± 8 to 434 ± 21 μg/hr. The half-life of [ 14C]choline-labeled phospholipids in the intracellular pool of surfactant was increased from 10.1 ± 1.0 to 18.3 ± 5.3 hr and that in the extracellular surfactant pool from 14.8 ± 1.4 to 21.9 ± 4.9 hr. Expansion of the intra- and extracellular pools of surfactant phospholipids may be explained on the basis of a metabolic imbalance in which the intracellular production of surfactant is increased above its secretion rate into the extracellular compartment, and the secretion rate is elevated above the rate at which surfactant phospholipids are cleared from the alveoli.

The accumulation of cystamine and its metabolism to taurine in rat lung slices

The objective of these studies was to determine the accumulation and fate of the disulphide, cystamine by rat lung slices. Cystamine was accumulated by two active uptake systems that obeyed saturation kinetics, with apparent K m values of 12 and 503 μM, and maximal rates of 530 and 5900 nmol/g wet weight/hr respectively. The high affinity system was competitively inhibited by the diamine, putrescine and the herbicide paraquat, which are themselves accumulated. Thus, this pulmonary uptake process appears to be identical for all three compounds. In contrast, the low affinity process was not inhibited by putrescine, and this process results from the diffusion of cystamine into the cell and its subsequent metabolism. Upon accumulation, cystamine was metabolised, predominantly to the sulphonic acid, taurine, with 10–20% of the intracellular label covalently binding to protein. Conversion to taurine was unaffected by amine oxidase inhibitors, but was decreased after GSH depletion, suggesting that pulmonary cystamine metabolism is glutathione-dependent, and is not mediated by diamine oxidase. Both cystamine and taurine have been implicated as antioxidants, and we suggest that cystamine is actively accumulated by the lung as part of the process to protect pulmonary tissue against oxidative stress.

Endothelin produces pulmonary vasoconstriction and systemic vasodilation

Endothelin is a newly described polypeptide derived from endothelial cells. The effects of porcine endothelin on the pulmonary vascular bed and systemic vascular bed were investigated in the anesthetized, intact-chest cat under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of porcine endothelin (100-1000 ng) produced a mild vasoconstrictor response in the pulmonary vascular bed. The pulmonary vasoconstrictor response to endothelin was not altered when pulmonary vasomotor tone was increased by infusion of U46619. In contrast to this mild pulmonary vasoconstrictor response, endothelin decreased systemic arterial pressure. Moreover, injections of porcine endothelin into the right and left atria produced similar reductions in aortic pressure as well as similar increases in cardiac output and decreases in systemic vascular resistance. The systemic vasodilator response to porcine endothelin was not affected by beta 2-adrenoceptor blockade. The present data suggest that endothelin does not undergo significant first-pass pulmonary metabolism. The pulmonary vasoconstrictor response to bolus injections of porcine endothelin is not altered by changes in pulmonary vasomotor tone. In contrast, endothelin markedly dilated the systemic vascular bed independently of activation of beta 2-adrenoceptors. The present study provides the first report of the activity of endothelin on pulmonary and systemic hemodynamics in vivo. Moreover, the potent vasodilator activity of endothelin in the systemic vascular bed and its weak effect on pulmonary vessels suggest that endothelin may be more important in the regulation of peripheral vasomotor tone than the pulmonary vascular bed.

Long-lasting effects of tobacco smoking on pulmonary drug-metabolizing enzymes: A case-control study on lung cancer patients : Petruzzelli S, Camus A.-M, Carrozzi L. CNR Institute of Clinical Physiology, Second Medical Clinic, University of Pisa, Pisa. Cancer Res 1988;48:4695–4700

Lung tissue specimens were taken during surgery from middle-aged men with either lung cancer (LC, n = 54) or a nonneoplastic lung disease (n = 20). Aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECDE), epoxide hydrolase (EH), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT) activities and glutathione and malondialdehyde contents were determined in 12,000 X g supernatant fractions from nontumorous parenchymal tissues. Interindividual differences in enzyme activities ranged from 11- to 440-fold, and glutathione content varied by 17-fold; the values showed unimodal distributions. AHH, ECDE, EH, and UDPGT activities were significantly and positively correlated to each other; a significant negative correlation was found between GST and the other enzymes. A relationship between enzyme activity and number of cigarettes smoked (pack-years) was found only for GST. Ignoring detailed smoking histories in the 6-month period preceding surgery, no difference was found in enzyme activities or glutathione content between LC and nonneoplastic lung disease patients or between smokers and nonsmokers. However, when the number of days since stopping smoking was considered, in smokers a significant increase was found for AHH, EH, and UDPGT activities and a significant decrease was found for GST activity, as compared to nonsmokers. LC patients who had smoked until the day before surgery had higher activities of AHH, ECDE, EH, and UDPGT than nonsmokers, while GST activity was reduced by one-third. The activities of these enzymes returned to the basal level found in nonsmokers within 59 (AHH), 108 (EH), 67 (UDPGT), and 40 (GST) days. LC patients who were recent smokers (within 30 days prior to surgery) had significantly induced AHH and ECDE activities when compared with smoking nonneoplastic lung disease patients. These results show that pulmonary drug metabolism can be altered by tobacco smoking and that these effects can last 40 to 108 days after cessation of smoking. These new findings should be considered in studies on the role of carcinogen-metabolizing enzymes in determining susceptibility to lung cancer.

Cell specificity for the pulmonary metabolism of tobacco-specific nitrosamines in the Fischer rat.

The activity and distribution of the metabolic pathways of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the structurally related nitrosamine, N'-nitrosonornicotine (NNN) were examined in pulmonary cells from F344 rats in order to investigate the mechanisms by which NNK and NNAL, but not NNN, cause lung tumors. The tritium labeled nitrosamines were incubated with Clara cells, alveolar macrophages, alveolar type II cells, or small cells and metabolites were analyzed by HPLC. O6-Methyl-guanine (O6MG) formation was also quantified in the cells incubated with NNK. Clara cells metabolized all compounds more extensively than the other cell types. Total alpha-hydroxylation, carbonyl reduction to NNAL, and pyridine N-oxidation in cells incubated with NNK, as well as concentrations of O6MG in DNA were higher in Clara cells than in other cell types. Carbonyl reduction of NNK predominated over the other metabolic pathways in all cell types. The high activity for alpha-hydroxylation of NNK in Clara cells is consistent with previous studies which proposed that the cell specificity for O6MG formation and the accumulation of this adduct during low-dose exposure to NNK may stem from the presence of a high affinity pathway in Clara cells for NNK activation. Metabolism of NNAL by alpha-hydroxylation, and by reconversion to NNK followed by alpha-hydroxylation were observed. Total alpha-hydroxylation of NNAL was less extensive than alpha-hydroxylation of NNK. NNN was metabolized by both the 2'- and 5'-alpha-hydroxylation pathways. 2'-Hydroxylation of NNN produces the same DNA pyridyloxobutylating agent as does methyl hydroxylation of NNK. However, NNN is not a methylating agent and does not induce lung tumors in rats. Metabolism of NNN by 2'-hydroxylation was, depending on cell type, 41-85% as extensive as total alpha-hydroxylation of NNK, indicating that the rates of formation of the DNA pyridyloxobutylating agent were similar from NNN and NNK. The results of this study demonstrate that Clara cells have a high capacity to metabolically activate NNK, NNAL and NNN and provide further support for the hypothesis that DNA methylation of pulmonary cells is important in NNK carcinogenesis.

Lack of influence of butylated hydroxytoluene on modification of lung microsome mediated aflatoxin B 1-DNA binding: role of pulmonary glutathione S-transferase

Phenolic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are known to inhibit tumor formation due to several chemical carcinogens including aflatoxin B 1 (AFB 1). Metabolic activation of AFB 1 by lung microsomes and possible modification by dietary BHA was reported in an earlier communication (Allameh et al. (1988) Cancer Lett., 40, 49). Here we report the effect of dietary BHA at a high dose (0.75% for 15 days) and a low dose (0.06% for 180 days) on the activation and inactivation of AFB 1 by subcellular preparations of lung. BHT at high dose alone induced hepatic cytosolic glutathione (GSH) S-transferases activity while the pulmonary enzyme was unaffected by BHT feeding. This observation was substantiated when the addition of lung cytosol from control and BHT-treated rats showed similar inhibition (50%) in the microsome mediated AFB 1-DNA binding. Thus BHT appears to have little influence on the pulmonary metabolism of AFB 1.