NADPH-dependent metabolism of estrone by human liver microsomes

We characterized the NADPH-dependent metabolism of estrone (E1) by liver microsomes of 21 male and 12 female human subjects. The structures of 11 hydroxylated or keto metabolites of E1 formed by human liver microsomes were identified by chromatographic and mass spectrometric analyses. 2-Hydroxylation of E1 was the dominant metabolic pathway with all human liver microsomes tested. E1 is more prone to form catechol estrogens (particularly 4-OH-E1) than 17beta-estradiol (E2) and the average ratio of E1 4-hydroxylation to 2-hydroxylation (0.24) was slightly higher than the ratio of E2 4- to 2-hydroxylation (0.20, P < 0.001). An unidentified monohydroxylated E1 metabolite (y-OH-E1) was found to be one of the major metabolites formed by human liver microsomes of both genders. 6beta-OH-E1, 16alpha-OH-E1, and 16beta-OH-E1 were also formed in significant quantities. 16alpha-hydroxylation was not a major pathway for E1 metabolism. The overall profiles for the E1 metabolites formed by male and female human liver microsomes were similar, and their average rates were not significantly different. Hepatic CYP3A4/5 activity in both male and female liver microsomes correlated strongly with the rates of formation of several hydroxyestrogen metabolites. The dominant role of hepatic CYP3A4 and CYP3A5 in the formation of these hydroxyestrogen metabolites was further confirmed by incubations of human CYP3A4 or CYP3A5 with [3H]E1 and NADPH. Notably, human CYP3A5 has very high relative activity for E1 4-hydroxylation, exceeding its activity for E1 2-hydroxylation by approximately 100%. It will be of interest to determine the potential biological functions associated with any of the E1 metabolites identified in our present study.     

Decreased leukotriene B4 synthesis in smokers' alveolar macrophages in vitro

Recent studies have shown that alveolar macrophages (AM) are able to release leukotrienes (LTs). Since cigarette smoking inhibits the cyclooxygenase pathway of arachidonic acid metabolism in the AM, we evaluated the LT production by AM from smokers and nonsmokers. AM were obtained from 35 volunteers, 16 nonsmokers, and 19 smokers. The cells were incubated under various conditions including stimulation with 30 microM arachidonic acid, 2 microM ionophore A23187, or both. Each experiment was performed in parallel using cells from a smoker and a nonsmoker. Lipoxygenase products were analyzed by reverse-phase high performance liquid chromatography. After stimulation, nonsmokers' AM produced LTB4 and 5-hydroxy-eicosatetraenoic acid (5-HETE). In incubations of AM with arachidonic acid and ionophore, the amounts of products formed were: LTB4, 317 +/- 56 pmol/10(6) cells and 5-HETE, 1,079 +/- 254, mean +/- SEM. No metabolites were generated under control conditions (no stimulation). In all incubations performed, the peptido-LTs (LTC4, LTD4, and LTE4) were undetectable. In comparison with AM from nonsmokers, those from smokers showed a 80-90% reduction of 5-HETE and LTB4 synthesis (P less than 0.05 to P less than 0.001 according to stimulatory conditions). This defective lipoxygenase metabolite production in AM from smokers was observed over a wide range of stimuli concentrations and incubation times; AM from smokers also had lower levels of intracellular (esterified) 5-HETE than nonsmokers' AM. We also studied blood polymorphonuclear leukocytes (PMNL) and no difference in the synthesis of 5-lipoxygenase products in these cells was noticed between smokers and nonsmokers. These data show that cigarette smoking causes a profound inhibition of the 5-lipoxygenase pathway in AM but not in blood PMNL.     

Characterization of the NADPH-dependent metabolism of 17beta-estradiol to multiple metabolites by human liver microsomes and selectively expressed human cytochrome P450 3A4 and 3A5.

We characterized the NADPH-dependent metabolism of 17beta-estradiol (E2) by liver microsomes from 21 male and 12 female human subjects. A large number of radioactive estrogen metabolite peaks were detected following incubations of [3H]E2 with male or female human liver microsomes in the presence of NADPH. The structures of 18 hydroxylated or keto estrogen metabolites formed by these microsomes were identified by gas chromatography/mass spectrometry analysis. 2-Hydroxylation (the formation of 2-OH-E2 and 2-OH-E1) was the dominant metabolic pathway with all human liver microsomes tested. The average ratio of 4-OH-E2 to 2-OH-E2 formation was approximately 1:6. A new monohydroxylated E2 metabolite (chemical structure unidentified) was found to be one of the major metabolites formed by human liver microsomes of both genders. 6beta-OH-E2 and 16beta-OH-E2 were also formed in significant quantities, but products of estrogen 16alpha-hydroxylation (16alpha-OH-E2 + 16alpha-OH-E1) were quantitatively minor metabolites. In addition, many other estrogen metabolites such as 6-keto-E2, 6alpha-OH-E2, 7alpha-OH-E2, 12beta-OH-E2, 15alpha-OH-E2, 15beta-OH-E2, 16beta-OH-E1, and 16-keto-E2 were also formed in relatively small quantities. The overall profiles for the E2 metabolites formed by male and female human liver microsomes were similar, and their average rates were not significantly different. The activity of testosterone 6beta-hydroxylation (a selective probe for CYP3A4/5 activity) strongly correlated with the rate of formation of 2-OH-E2, 4-OH-E2, and several other hydroxyestrogen metabolites by both male and female liver microsomes. The dominant role of hepatic CYP3A4 and CYP3A5 in the formation of these hydroxyestrogen metabolites was further confirmed by incubations of selectively expressed human CYP3A4 or CYP3A5 with [3H]E2 and NADPH.     

Facilitated nitration and oxidation of LDL in cigarette smokers

BACKGROUND: Cigarette smoking increases the risk of developing atherosclerosis and ischaemic heart disease. Smoking-induced oxidative stress is considered to favour oxidation of low-density lipoprotein (LDL) and subsequently promotes the atherogenic process. We investigated whether peroxynitrite, a reaction product of cigarette smoke, is involved in facilitated oxidation of LDL in smokers. MATERIALS AND METHODS: Plasma LDL was obtained from 10 healthy asymptomatic cigarette smokers and 10 healthy nonsmokers. The state of enhanced oxidative stress in the plasma was assessed by LDL subfraction assay using anion-exchange high-performance liquid chromatography (AE-HPLC) and measurements of thiobarbituric acid-reactive substances (TBARS), 8-hydroxydeoxyguanosine (8-OHdG), vitamin E, 3-nitrotyrosine and 3-chlorotyrosine. RESULTS: Smokers showed a significantly higher level of TBARS and 8-OHdG as well as a significantly lower level of vitamin E than nonsmokers, even after stopping smoking for 10 h or more. The LDL subfraction assay demonstrated an increase in oxidatively modified LDL, as expressed by lower levels of LDL1 and higher levels of LDL2. The 3-nitrotyrosine levels in apolipoprotein B in LDL were significantly higher in smokers than nonsmokers, while the 3-chlorotyrosine levels remained unchanged. In addition, these changes observed in the smokers were further accelerated within 30 min after resumption of cigarette smoking when compared with the levels before smoking resumption. CONCLUSION: The present study suggests that peroxynitrite plays a significant role in oxidative modification of plasma LDL induced by cigarette smoking.     

Cigarette Smoking does not Induce Plasma or Pulmonary Oxidative Stress after Moderate-intensity Exercise

[Purpose] Cigarette smoking increases oxidative stress, which is a risk factor for several diseases. Moreover, strenuous exercise has been shown to induce plasma and pulmonary oxidative stress in young cigarette smokers. However, no previous reports have demonstrated whether plasma and pulmonary oxidative stress occur after moderate-intensity exercise. Therefore, the aim of this study was to clarify whether moderate-intensity exercise induces pulmonary and plasma oxidative stress in smokers. [Subjects] Ten young male smokers and 10 young male nonsmokers participated in this study. [Methods] Plasma hydroperoxide concentrations were measured at baseline and then immediately and 15 min after moderate-intensity exercise. Hydrogen peroxide concentrations in exhaled breath condensate were measured at baseline and after exercise. [Results] No significant interactions were found between smokers and nonsmokers in terms of hydroperoxide or hydrogen peroxide concentrations following moderate-intensity exercise at any time point. [Conclusion] These findings suggested that moderate-intensity exercise did not induce plasma or pulmonary oxidative stress in young cigarette smokers.Key words: Oxidative stress, Cigarette smoker, Moderate-intensity exercise     

Effect of cigarette smoking on the oxidant/antioxidant balance in healthy subjects

BACKGROUND AND PURPOSE: Cigarette smoking has been associated with the development of cardiovascular disease and cancer. Even though the molecular mechanism(s) are not clear, the pathology has been related to oxygen free radicals present in cigarette smoke. Thus, the main objective of this study was to establish the changes in the oxidation/antioxidation balance induced by cigarette smoking. METHODS: Thirty healthy subjects (15 smokers and 15 nonsmokers) of both sexes were studied. The smokers group had smoked a mean of 14 cigarettes per day for an average of 4.5 years. Fasting serum levels of malondialdehyde (MDA), a marker of oxidative stress, nitric oxide (NO), reduced glutathione (GSH), and vitamin C (ascorbic and dehydroascorbic acids) were measured. RESULTS: Fasting NO concentration was significantly higher in smokers (51.3 +/- 5.3 microM) than in nonsmokers (35.2 +/- 4.8 microM, P < 0.05). The smokers had significantly higher serum dehydroascorbic acid levels (2.4 +/- 0.5 mg/dL, P < 0.03) than the nonsmokers (1.08 +/- 0.08 mg/dL). No significant differences were observed in the levels of ascorbic acid, MDA, and GSH between the smokers and nonsmokers. CONCLUSIONS: Our results suggest that exposure to cigarette smoke increases NO synthesis, such that NO may act in a compensatory way as an inhibitor of lipid peroxidation. Smoking also activates other antioxidative mechanisms such as involving vitamin C. These protective mechanisms appear to be enough in preventing accumulation of oxidative products such as MDA and avoiding oxidative damage.     

The health consequences of cigarette smoking. Pulmonary diseases.

Cigarette smoking has significant detrimental effects on both the structure and function of the lung; it is the single most important risk factor for the development of COPD. Uncertainty remains concerning the mechanisms by which smokers develop obstructive lung disease. It is speculated, however, that an imbalance between proteolytic and antiproteolytic forces in the lung or an increase in heightened airways responsiveness is responsible. Population-based studies have documented lower levels of FEV1, accelerated loss of ventilatory function, and increased respiratory symptoms and infections among smokers compared with nonsmokers. Data from both prospective and retrospective studies have consistently shown increased mortality from COPD, pneumonia, and influenza among cigarette smokers compared with nonsmokers.     

Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men

The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.     

The effect of cigarette smoking on salivation and esophageal acid clearance

To further define the influence of cigarette smoking on the pathophysiology of gastroesophageal reflux disease, studies were done to evaluate acid clearance in the esophagus and the salivary titratable base secretion of chronic smokers as compared to those of nonsmokers, and to ascertain the acute effects of smoking on these variables. Eight nonsmoking volunteers and 16 cigarette smokers without symptoms of gastroesophageal reflux disease were studied. All studies were initiated after a 6-hour fast, with the smokers also having refrained from smoking. Of the 16 smokers half smoked three cigarettes in the course of the experiments and half did not smoke. The immediate effects of cigarette smoking were a prolongation of the acid clearance time and a diminution of the secretion of salivary titratable base. However, both of these effects were overshadowed by greater baseline differences between the populations of smokers and nonsmokers. As a population the smokers had only 60% of the titratable base secretion of nonsmokers and acid clearance times that were 50% longer than those of nonsmokers. These effects were presumably long-lasting effects of cigarette smoking, although the duration of the effect was not defined. The observed differences in acid clearance are most likely the result of diminished salivary base secretion, since good correlation existed between these parameters.     

Cigarette smoking and the risk of gestational and pregestational diabetes in two consecutive pregnancies

OBJECTIVE: Cigarette smoking during pregnancy may increase the risk of gestational diabetes mellitus (GDM) or pregestational diabetes mellitus (PDM). Smoking has been associated positively with hyperinsulinemia and insulin resistance in experimental studies, although the association with diabetes remains unclear. To further explore this issue, we examined the association with smoking in the largest prospective cohort study of GDM and PDM to date. RESEARCH DESIGN AND METHODS: The study population comprised 212190 women in the population-based Swedish Birth Registry who had their first and second deliveries between January 1987 and December 1995. Maternal characteristics were recorded in a standardized manner at the first prenatal visit, followed by a clinical examination and a standardized in-person interview to assess lifestyle habits. Women were categorized as nonsmokers, light smokers (one to nine cigarettes per day), or moderate-to-heavy smokers (at least 10 cigarettes per day). RESULTS: Women with GDM in their first pregnancy experienced an eight- to ninefold increased risk of GDM or PDM in their second pregnancy. Cigarette smoking was not associated with increased risk of these conditions. Neither women who smoked during their first and second pregnancies nor those who commenced smoking between pregnancies had a higher risk of GDM or PDM than nonsmokers. CONCLUSIONS: Our findings do not support an association between cigarette smoking and risk of GDM or PDM in young women of childbearing age.     

Disposition of nicotine and eight metabolites in smokers and nonsmokers: identification in smokers of two metabolites that are longer lived than cotinine

The disposition of a single intravenous dose of 14C-nicotine was investigated in six cigarette smokers and six nonsmokers. Plasma and urinary elimination of both nicotine and cotinine was faster in smokers than in nonsmokers. In the urine of both smokers and nonsmokers, we identified nicotine and eight metabolites, including two new metabolites: metabolite A (3-hydroxycotinine glucuronide) and metabolite G (demethylcotinine delta 2',3'-enamine). Metabolites A and G were of particular interest because, in smokers, they both persisted longer than cotinine. This property renders them more sensitive than cotinine as potential indicators of passive exposure to cigarette smoke.     

Transdermal nicotine mimics the smoking-induced endothelial dysfunction

BACKGROUND: Cigarette smoking is a major risk factor for coronary artery disease and causes endothelial dysfunction, perhaps by decreasing the availability of nitric oxide availability in arteries and veins. Nicotine in cigarette smoke may be responsible for this impaired endothelial response. METHODS: We studied nine healthy nonsmokers and 12 healthy mild to moderate smokers by use of the dorsal hand vein compliance technique. Dose-response curves to bradykinin and sodium nitroprusside were obtained to test the endothelium-dependent and endothelium-independent vasorelaxation before and during the use of a nicotine (21 mg) patch. Mean arterial blood pressure and heart rate were measured beat-to-beat during the 4-hour study and serial blood samples were drawn to assay plasma thromboxane B2 levels. RESULTS: Transdermal nicotine reduced the venous responsiveness to bradykinin in nonsmokers (Emax = 88.0% +/- 17.9% and 54.3% +/- 14.9%, respectively, before and after the nicotine patch; P < .05); the latter response was similar to that in smokers (Emax = 56.3% +/- 16.6%). Sodium nitroprusside-induced venodilation was unaltered. Mean arterial blood pressure increased in both smokers and nonsmokers. Transdermal nicotine increased the plasma thromboxane B2 concentrations only among nonsmokers. CONCLUSION: These findings indicate that nicotine can have a major role in the impaired endothelial function in smokers. The results probably also reflect what occurs in arterial beds because the nicotine patches increased the mean arterial blood pressure in both smokers and nonsmokers.     

Effects of smoking on cardiopulmonary baroreceptor activation and peripheral vascular resistance

PATIENTS AND METHODS: We studied 16 healthy smokers and 16 nonsmokers acting as controls. We subjected smokers and nonsmokers to cardiopulmonary baroreceptor stimulation by studying forearm and common carotid haemodynamic and sympathovagal balance. Smokers repeated the tests after smoking one cigarette. Smokers and controls were subjected to passive elevation of the legs and the trunk in a horizontal position with pressure monitoring and measurement of the calibre and flow in the brachial and common carotid arteries using a colourDoppler ultrasound. We calculated forearm resistance and carotid wall tension. We also studied R-R variability, calculating the ratio between low frequency (LF) and high frequency (HF) R-R interval variability. RESULTS: During stimulation diastolic blood pressure values decreased in controls and in smokers at rest. After smoking one cigarette, smokers showed an increase in systolic and diastolic blood pressure as well as in the heart rate during stimulation. Humeral artery increased the calibre during stimulation in both groups; after cigarette smoking the calibre declined throughout the study phases. Forearm resistance decreased in both groups during stimulation at rest, but increased after cigarette smoking. The LF/HF ratio decreased during stimulation in both groups, and it increased at rest after smoking. Carotid diameter did not change in either group, and wall tension increased in smokers after smoking one cigarette. CONCLUSIONS: Smoking one cigarette increases resistance, impairs baroreflex and increases carotid wall tension in mild smokers. These findings may explain the higher rate of a cardiovascular event in smokers.     

Cigarette smoking and theophylline metabolism: effects of phenytoin

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 +/- 2.0 micrograms/ml) and smokers (11.5 +/- 0.9 micrograms/ml). Control theophylline elimination half-life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half-life (26.8% +/- 5.6% in smokers and 25.8% +/- 3.5% in nonsmokers) and clearance (48.0% +/- 10.1% in smokers and 39.7% +/- 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.     

Cigarette smoking and drug metabolism

Cigarette smoking appeared to induce total body drug metabolism, as indicated by decreased antipyrine t 1/2 and increased antipyrine clearance. The in vitro parameters of liver drug metabolism used (benzo(a)pyrene hydroxylase and cytochrome P-450 levels), however, were not changed. This implicates induction of drug metabolism in some other organ(s). Serum thiocyanate levels were higher in smokers than in exsmokers and nonsmokers. There was a certain amount of overlap between these groups; whether this reflects unreliability of smoking anamnesis or unspecificity of thiocyanate assay in discriminating between smokers and nonsmokers is not known. There was no significant correlation between serum thiocyanate and the other parameters studied.     

The health consequences of smoking. Cancer.

Smoking has now been identified as a definite cause of cancer at many sites (Table 2). Of all cancers in the United States, 30% could be prevented if cigarette smoking were eliminated. Organs in direct contact with smoke--the oral cavity, esophagus, lung, and bronchus--are at the greatest risk of malignancy among smokers. As many as 90% of these cancers are attributable to smoking. Organs and tissues distant from smoke are also at some increased risk. Among smokers, rates of cancer of the cervix, pancreas, bladder, kidney, stomach, and hematopoietic tissue are increased 50% to 200% over rates in nonsmokers. Risk of cancer at all sites increases with increasing exposure to cigarette smoke. Cigarette smoke contains potent carcinogens that influence carcinogenesis at both early and late stages. These carcinogens can interact with other exposures, such as alcohol, to synergistically increase the risk of cancer. The adverse carcinogenic effects of cigarette smoking, however, can be reduced for all smokers if tobacco use is stopped. The prevalence of smoking among the US population as a whole has declined from 40% in 1965 to 29% in 1987. This progress against the epidemic of tobacco use has already produced a decrease in the occurrence of the most common tumor among men, lung cancer. Unfortunately, the decline in smoking prevalence and cancer incidence has not occurred equally across US populations. Death rates of lung cancer in women continue to rise, and, based upon current smoking patterns, these rates will continue to increase into the next century. The challenge to physicians and public health workers is compelling and immediate: Abstaining from smoking is the single most effective way to reduce an individual's risk of cancer.     

Active Smoking and Hematocrit and Fasting Circulating Erythropoietin Concentrations in the General Population

Cigarette smoking continues to be one of the major risk factors for increased morbidity and mortality worldwide. Among many adverse health effects, smoking can induce erythrocytosis, which is commonly believed to result from elevated serum erythropoietin (EPO) levels. Currently, however, this notion is only alleged, without data available to substantiate it. Hence, we analyzed data from the Prevention of Renal and Vascular End-Stage Disease study, a prospective population-based cohort study. Smoking behavior was quantified as number of cigarettes smoked per day and as 24-hour urinary cotinine excretion levels, an objective and quantitative measure of nicotine exposure. In 6808 community-dwelling participants, the prevalence of nonsmokers, former smokers, and current smokers were 29%, 43%, and 28%, respectively. Hematocrit levels were higher in current smokers (41.4%±3.6%) than in nonsmokers (40.3%±3.6%) (P<.001). In contrast, median EPO levels were lower in current smokers (7.5 IU/L; interquartile range [IQR], 5.7-9.6 IU/L) than in nonsmokers (7.9 IU/L; IQR, 6.0-10.7 IU/L) (P<.001). In multivariate linear regression analysis, current smoking, compared with nonsmoking, was independently positively associated with hematocrit levels (β=.12; P<.001) and hemoglobin levels (β=.11; P<.001), but inversely associated with EPO levels (β=?.09; P<.001). In sensitivity analyses, we observed a dose-dependent inverse association of smoking exposure reflected by 24-hour urinary cotinine excretion levels with EPO levels. Contrary to common belief, we identified that in the general population, smoking is inversely associated with EPO levels. Future mechanistic insight is needed to unravel the currently identified association, and if reproduced in other studies, guidelines for diagnosis of secondary erythrocytosis may need to be revisited.     

Acute effect of cigarette smoking on serum angiotensin-converting enzyme activity in normal man

The acute effect of cigarette smoking on serum angiotensin-converting enzyme activity was evaluated in 6 healthy subjects consisting of 4 non-smokers and 2 habitual smokers. Cigarette smoking resulted in rapid increases in serum converting enzyme activity in 5 of 6 subjects within 5 min. and the converting enzyme activity remained above the control value at 30 min. The increase in the enzyme activity of non-smokers was higher than that of habitual smokers at any time when the enzyme activity was determined. It is therefore suggested that cigarette smoke (or smoking) can cause the secretion of angiotensin-converting enzyme from the pulmonary endothelial cell, in which the enzyme may be produced, to the systemic circulation. It is also speculated that the increase in the enzyme activity may contribute to the initiation of cardiovascular changes associated with cigarette smoking.     

Aging and drug interactions. I. Effect of cimetidine and smoking on the oxidation of theophylline and cortisol in healthy men

The effect of age on the inhibition of theophylline metabolism was investigated in young and old male cigarette smokers (greater than 20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) during days 1 to 7 or 8 to 14. On days 7 and 14, a tracer dose (10 mg i.v.) of stable isotope-labeled theophylline was administered with the oral dose of theophylline. Plasma clearance in old nonsmokers was 33% less than in young nonsmokers. Values in both young and old smokers were not significantly different but exceeded those in non-smokers. Because volume of distribution was similar in all groups, the half-lives were prolonged in proportion to the decrease in clearance. Although smoking was associated with selective induction of the formation of 3-methylxanthine and 1-methyluric acid, the effect of cimetidine was nonselective and the proportionate inhibitory effects of cimetidine on theophylline metabolism did not differ with age or smoking status. The excretion of 6 beta-hydroxycortisol was similar in smokers and non-smokers but was slightly inhibited by cimetidine. Cimetidine also reduced the interindividual variation in the absorption of theophylline. Despite a reduction in the basal oxidative capacity in healthy male nonsmokers, these results indicate that both the induction of theophylline metabolism by smoking and the inhibition of theophylline metabolism by cimetidine are preserved in old age.