Effects of cigarette smoking and exposure to cadmium and lead on phenotypic variability of hepatic CYP2A6 and renal function biomarkers in men

Effects of cigarette smoking and exposure to dietary cadmium (Cd) and lead (Pb) on urinary biomarkers of renal function and phenotypic variability of cytochrome P450 2A6 (CYP2A6) were investigated in a group of 96 healthy Thai men with mean age of 36.7 year (19-57 years). In non-smokers, Cd burden increased with age (r = 0.47, P < 0.001). In current smokers, Cd burden increased with both age (r = 0.45, P = 0.01) and number of cigarettes smoked per day (r = 0.32, P = 0.05). Cd-linked renal tubular dysfunction was seen in both smokers and non-smokers, but Pb-linked glomerular dysfunction was seen in smokers only, possibly due to more recent exposure to high levels of Cd and Pb, as reflected by 30-50% higher serum Cd and Pb levels in smokers than non-smokers (P < 0.05). Exposure to dietary Cd and Pb appeared to be associated with mild tubular dysfunction whereas dietary exposure plus cigarette smoking was associated with tubular plus glomerular dysfunction. Hepatic CYP2A6 activity in non-smokers showed a positive association with Cd burden (adjusted beta = 0.38, P = 0.006), but it showed an inverse correlation with Pb (adjusted beta = -0.29, P = 0.003), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. In contrast, CYP2A6 activity in current smokers did not correlate with Cd or Pb, but it showed a positive correlation with serum ferritin levels (r = 0.45, P = 0.01). These finding suggest that Pb concentrations in the liver probably were too low to inhibit hepatic synthesis of heme and CYP2A6 and that the concurrent induction of hepatic CYP2A6 and ferritin was probably due to cigarette smoke constituents other than Cd and Pb.     

Effect of smoking on cadmium and lead concentrations in human amniotic fluid

The amniotic fluids of 155 pregnant women, non-smokers (n = 128) and smokers (n = 27), were investigated on their cadmium (Cd) and lead (Pb) concentrations. The mean +/- s range of Cd in the amniotic fluid of non-smokers amounted to 2.58 +/- 1.36 ng/l, that of smokers to 7.29 +/- 2.39 micrograms/l. Moreover, there was a correlation between the extent of daily cigarette consumption and Cd levels. With Pb, higher concentrations were found ranging between 23.98 +/- 9.41 ng/l for non-smokers and 21.53 +/- 7.16 micrograms/l for smokers. No correlations were seen between age, week of pregnancy, blood pressure, disorders of pregnancy and the amniotic Cd or Pb concentrations. Thus, the maternal and fetal risks of the higher Cd levels in the amniotic fluid of smoking women remain unanswered.     

The influence of smoking on the intersubject variation in pentazocine elimination.

The cumulative urinary excretion over 24 h of pentazocine, under conditions of acidic urinary pH, has been measured in smokers and non-smokers using both male and female subjects (seventy subjects in total). A restricted urban population was studied. An overall three-fold inter-subject variation in elimination was observed. The cumulative urinary excretion of pentazocine was normally distributed in both smokers and non-smokers. Smokers metabolize 40% more pentazocine than non-smokers. It is concluded that induction is principally responsible for the observed subject variability.     

Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 microg/g and 3.8 microg/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi2 = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48, P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54, P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary Cd excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden.     

Susceptibility and exposure biomarkers in people exposed to PAHs from diesel exhaust

Xenobiotic metabolizing enzymes, especially CYP1A1 and GSTM1, are involved in the activation and conjugation of PAHs and are controlled by polymorphic genes. PAHs released from diesel emissions in many cities of the world, especially in developing countries, contribute significantly to the toxic effects of airborne inhalable particles. We have evaluated the gene-environment interaction in Santiago of Chile, studying the contribution of CYP1A1 and GSTM1 polymorphisms on 1-OH-P urinary levels used as the PAHs exposure biomarker. The study was performed on 59 diesel exposed (38 diesel revision workers and 21 subjects working in an urban area as established street vendors) and 44 non-exposed subjects living in a rural area. The 1-OH-P urinary levels of the urban (P=0.043) and rural (P=0.040) populations showed, without considering the genotypes, significant differences between smokers and non-smokers, but no significant differences were found between smokers and non-smokers among the diesel plant workers (P=0.33). Non-smoking subjects of the diesel plants and the urban area showed similar 1-OHP levels (P=0.466) which were significantly higher than those of the subjects living in the rural area (P<0.05). When 1-OH-P levels were related with genotypes, an association was observed for the CYP1A1*2A genotype, so that the diesel-exposed workers carrying the CYP1A1*2A allele showed significantly higher 1-OH-P levels than the subjects from the rural area with the same genotype (P=0.008). On the other hand, there was no significant correlation between urinary 1-OH-P levels and GSTM1 null genotype, although higher levels of the urinary metabolite were found in individuals carrying the combined CYP1A1*2A and GSTM1 null genotype (P=0.055). These results may suggest an association between levels of the exposure biomarker 1-OH-P and presence of the CYP1A1*2A genotype, a potential genetic susceptibility biomarker which might be useful in identifying individuals at higher risk among people exposed to high PAH levels in diesel exhaust.     

Increased urinary cadmium excretion and its relationship to urinary N-acetyl-β-d-glucosaminidase activity in smokers

To assess the renal effects of low-level exposure to cadmium due to smoking we examined blood and urinary levels of cadmium and urinary excretions of N-acetyl--d-glucosaminidase (NAG), ₂-microglobulin (BMG) and metallothionein in 94 male workers aged 18–55 years. Both blood and urinary cadmium levels indicated excess exposure to cadmium caused by smoking. The urinary cadmium concentration ranged between 0.1 and 5.0 g/g creatinine and increased significantly with age in the smokers. Neither urinary NAG nor BMG was increased in the smokers compared from non-smokers. A positive relationship between urinary cadmium and metallothionein was obtained not only in the smokers but also in the non-smokers. Furthermore, in the smokers urinary cadmium and metallothionein was positively related with urinary NAG. Since NAG in urine mostly originates from tubular cells by lysosomal exocytosis, the results may reflect an early cadmium effect on the lysosomal functions. Inhibitory effect of cadmium on the lysosomal degradation activities was discussed as a possible explanation of the positive relationship of urinary cadmium and metallothionein to urinary NAG.     

Hydroxy-phenanthrenes in the urine of non-smokers and smokers

Urinary hydroxy-phenanthrene (HO-PHE) excretion in non-smokers exposed to environmental tobacco smoke (ETS) is not increased. There is no significant difference in HO-PHE excretion between smokers (S) and non-smokers (NS), though excretion seems to be slightly elevated in smokers. A diet rich in polycyclic aromatic hydrocarbons leads to a rise in urinary HO-PHE excretion as compared to a diet low in polycyclic aromatic hydrocarbons (PAH), coming close to significance. HO-PHE excretion is not correlated with the mutagenic activity in urine.     

Urinary acrylamide metabolites as biomarkers for short-term dietary exposure to acrylamide.

It has previously been reported that heat-treated carbohydrate rich foods may contain high levels of acrylamide resulting in consumers being inadvertently exposed to acrylamide. Acrylamide is mainly excreted in the urine as mercapturic acid derivatives of acrylamide and glycidamide. In a clinical study comprising of 53 subjects, the urinary excretion of these metabolites was determined using solid-phase extraction and liquid chromatography with positive electrospray MS/MS detection. The median (range) total excretion of acrylamide in urine during 24 h was 16 (7-47) microg acrylamide for non-smokers and 74 (38-106) microg acrylamide for smokers, respectively. It was found that the median intake estimate in the study based on 24 h dietary recall was 21 (13-178) and 26 (12-67) for non-smokers and smokers, respectively. The median dietary exposure to acrylamide was estimated to be 0.47 (range 0.17-1.16) microg/kg body weight per day. In a multiple linear regression analysis, the urinary excretion of acrylamide metabolites correlated statistically significant with intake of aspartic acid, protein, starch and coffee. Consumption of citrus fruits correlated negatively with excretion of acrylamide metabolites.     

吸烟对2型糖尿病男性患者血糖控制的影响

目的：探讨吸烟对2型糖尿病男性患者空腹血糖（FBG）,餐后2 h 血糖（2hPBG）,糖化血红蛋白（HbA1 C）的影响。方法选取2型糖尿病男性患者142例,按吸烟情况分为不吸烟组（从不吸烟,n ＝44）,戒烟组（戒烟半年以上,n ＝33）,少量吸烟组（每天≤20支,n ＝33）,大量吸烟组（每天＞20支,n ＝32）,采用现场调查结合病例对照研究的方法,询问患者年龄、糖尿病病程、工作活动强度、吸烟、降糖药的应用等情况,测量血压、身高、体重、腰围、臀围,计算体重指数（BMI）、腰臀比（WHR）等指标,实验室检测葡萄糖（GLU）、2hPBG、HbA1 C,比较各组间血糖、糖化血红蛋白的差异;逐步回归及偏相关分析,了解吸烟对血糖控制影响的显著性及影响程度。结果（1）不吸烟组与大量吸烟组相比 FBG、2hPBG 明显降低（P ＜0．01）,HbA1 C 有所降低但差异无统计学意义（P ＞0．05）;不吸烟组与戒烟组比较2hPBG 有所升高（P ＜0．05或 P ＜0．01）;（2）少量吸烟组与大量吸烟组比较 FBG、2hPBG所降低但差异无统计学意义（P ＞0．05）;吸烟组与戒烟组相比 FBG、2hPBG、HbA1 C 均增高（P ＜0．05或P ＜0．01）;（3）吸烟是 HbA1 C 的独立危险因素（P ＜0．05,β＝－0．216）,FBG、2hPBG、HbA1 C 与日吸烟量、吸烟年限等无明显相关性（P ＞0．05）。结论吸烟是与年龄、BMI、工作活动强度、DM病程、用药情况等影响无关,为2型糖尿病男性患者血糖控制水平差的独立危险因素;吸烟组与戒烟组,戒烟组与不吸烟组之间血糖控制指标（FBG、2hPBG、HbA1 C）等的差异,表明大量吸烟不利于2型糖尿病男性患者血糖的控制,戒烟对2型糖尿病男性患者血糖控制有明显的积极的作用,在餐后血糖的控制上甚至优于从不吸烟患者。     

Cigarette smoking enhances the elimination of quinine

The pharmacokinetics of a single dose (600 mg) of quinine sulphate were examined in a group of non-smokers (n = 10) and in heavy cigarette smokers (n = 10). The mean (+/- s.d.) oral clearance of quinine in smokers (0.189 +/- 0.075 1 h(-1) kg(-1)) was significantly greater than in non-smokers (0.107 +/- 0.045 1 h(-1) kg(-1) , P < 0.01). The unbound clearance of quinine which reflects activity of the drug-metabolizing enzyme, was considerably greater (1.5-fold) in the smokers than in the non-smoker subjects. The mean elimination half-life of quinine in smokers was 7.5 +/- 1.4 (s.d.) h, significantly shorter (P < 0.005) than the mean value in non-smokers (12.0 +/- 3.1 h). These results suggest that cigarette smoking enhances the elimination of quinine. The clinical significance of these findings is unknown but they indicate the need for caution in the administration of quinine to patients who are heavy cigarette smokers.     

Effect of gender and cigarette smoking on urinary excretion of etheno DNA adducts in humans measured by isotope dilution gas chromatography/mass spectrometry

Endogenous formation of the promutagenic DNA adducts 1,N(6)-ethenoadenine (epsilon Ade) and 3,N(4)-ethenocytosine (epsilon Cyt) has been considered as biomarkers originated from lipid peroxidation. Elevated levels of epsilon Ade and epsilon Cyt were observed in cancer-prone tissues, suggesting the validity of these adducts in cancer risk assessment. The presence of DNA base adducts in biological fluids is considered to derive primarily from base excision repair (BER) systems. In this study, a modified gas chromatography/mass spectrometry (GC/MS) method is developed for simultaneous analysis of epsilon Ade and epsilon Cyt in human urine. After adjusting for creatinine concentration, urinary excretion of epsilon Ade, as well as epsilon Cyt, is much higher in 18 male smokers than in 10 male nonsmokers (p=0.003 for epsilon Ade and p=0.04 for epsilon Cyt). Furthermore, excretion of epsilon Ade and epsilon Cyt in 14 female nonsmokers is much higher than in 10 male nonsmokers (p=0.002 for epsilon Ade and p=0.005 for epsilon Cyt). These results suggest a statistically significant association between gender, as well as smoking, and excretion of epsilon Ade and epsilon Cyt. Moreover, urinary excretion of epsilon Ade in these 42 subjects correlates with that of epsilon Cyt (R(2)=0.6846, p<0.0001). Measurement of urinary epsilon Ade and epsilon Cyt excretion should provide valid noninvasive biomarkers for carcinogenesis and chemoprevention studies.     

Monitoring of cadmium toxicity in a Thai population with high-level environmental exposure

This study evaluated the utility of single and combined measurements of cadmium toxicity markers for surveillance purposes, using a sample of 224 individuals, 30-87 years of age, who were residents of cadmium polluted area in Mae Sot District, Tak Province, Thailand. Urinary cadmium levels excreted by them ranged between 1 and 58 microg/g creatinine with geometric mean of 8.2 microg/g creatinine which was 16-fold greater than the average for the general Thai population of 0.5 microg/g creatinine. The urinary markers evaluated were total protein, albumin, N-acetyl-beta-D-glucosaminidase (NAG), lysozyme, beta2-microglobulin (beta2-MG) and alpha1-microglobulin (alpha1-MG). Among these markers, only NAG showed a positive correlation with urinary cadmium in both male and female subjects with and without disease (r=0.43-0.71). Further, the prevalence rates for urinary NAG above 8 units/g creatinine (NAG-uria) increased with exposure levels in a dose dependent manner (p=0.05) among subjects with disease. In contrast, however, increased prevalence of beta2-MG above 0.4 mg/g creatinine (beta2-MG-uria) was associated with cadmium above 5 microg/g creatinine only in those without disease (POR=10.6 and 7.8 for 6-10 and >10 microg/g creatinine). Prevalence rates for abnormal excretion of all other markers, except albumin, were markedly increased among those having beta2-MG-uria with and without disease (chi2-test, p相似文献   

The relationships of urinary metallothionein with other indicators of renal dysfunction in people living in a cadmium-polluted area in Japan

An epidemiologic investigation was carried out to study the significance of urinary excretion of metallothionein (MT) in people aged 50 years and over living in a cadmium (Cd)-polluted area in Japan. The urinary level of MT was compared with various parameters (age, urinary alpha 1-microglobulin (alpha 1-MG), beta 2-microglobulin (beta 2-MG), total protein, Cd, copper (Cu), and zinc (Zn), and relative clearances to creatinine of alpha 1-MG, beta 2-MG, phosphate and uric acid). It was found that the urinary excretion of MT is closely associated with Cd and the indices of renal dysfunction listed above. This observation was more remarkable in women than men. When subjects with signs of renal dysfunction were compared as a group to those with normal renal functions, the excreted amount of MT in the former is significantly greater. The results support the notion that the urinary excretion of MT reflects not only Cd exposure levels but also renal dysfunction caused by long-term Cd exposure.     

Evaluation of lead exposure in battery‐manufacturing workers with focus on different biomarkers

The influence of exposure to lead on the frequency of micronuclei (MN), nuclear buds and nucleoplasmatic bridges was investigated in peripheral blood lymphocytes in 15 male battery‐manufacturing workers and 15 controls matched for age and smoking habits. In addition to MN test, blood lead (B‐Pb) and cadmium (B‐Cd), delta aminolevulinic acid dehydratase (ALAD) activity, erythrocyte protoporphyrin (EP), serum vitamin B₁₂ (S‐Vit B₁₂) and folate (S‐folate) were determined in all subjects. Lead‐exposed subjects had significantly higher MN frequency and B‐Pb concentrations than controls. In control smokers we found a significant negative correlation between B‐Pb concentration and frequency of nucleoplasmatic bridges, and nuclear division index. In control non‐smokers a significant positive correlation was observed only between age and nuclear buds frequency, and between S‐folate and B‐Pb level. In lead exposed smokers, significant positive correlations between MN frequency and S‐Vit B₁₂, S‐folate, and nuclear buds frequency were found. A positive correlation in exposed smokers was also found between nuclear buds frequency and S‐Vit B₁₂ concentration. A negative correlation was found between ALAD and EP, and B‐Pb in exposed smokers. Exposed non‐smokers showed significant negative correlation between MN frequency and B‐Cd, and ALAD and EP. The results indicate a genotoxicity of lead, pointing to a micronucleus assay as a relevant test for assessing genotoxic effects resulting from occupational exposure. The other indicators did not necessarily follow the results of THE MN test. Influence of smoking should be further investigated. Copyright © 2009 John Wiley & Sons, Ltd.     

Impact of smoking on the concentration and activity of alpha-1-antitrypsin in serum in relation to the urinary excretion of hydroxyproline

The impact of active and passive smoking on the serum levels of alpha 1-AT, the trypsin inhibitory capacity (TIC), the trypsin inhibitory activity (TIA) and the urinary hydroxyproline to creatinine ratio (HOP-ratio) was studied. The subjects used in the study on active smoking were 167 healthy adult men and in the study on passive smoking 189 healthy primary school children. Serum levels of alpha 1-AT in active smokers were significantly higher than those in non-smokers. The TIC as well as the TIA in active smokers decreased with increasing number of cigarettes smoked. The urinary HOP-ratio increased significantly with increasing number of cigarettes smoked. On the other hand, in the case of passive smokers a significant difference was obtained only for the HOP-ratio. The correlations between all markers in active smokers were significant. Less significant correlations were found in the case of passive smokers. These results suggest that the urinary excretion of hydroxyproline can be considered as a marker for the imbalance between proteases and anti-proteases as a result of smoking.     

The impact of antihypertensive drug groups on urinary albumin excretion in a non-diabetic population

AIMS: Microalbuminuria (30-300 mg 24 h-1) is recognized to be independently associated with renal and cardiovascular risk. Antihypertensives may lower microalbuminuria. We questioned whether the use of different antihypertensive drug classes in general practice influences microalbuminuria as related to blood pressure in nondiabetic subjects. METHODS: To study this, we used the data from 6836 subjects of an on-going population based study, focused on the meaning of microalbuminuria (PREVEND). Odds ratios, adjusted for age, sex, blood pressure, cholesterol level, smoking and the use of other antihypertensive or cardiovascular drugs, were calculated to determine the association of drug groups with microalbuminuria. Influence of antihypertensives on the relation between blood pressure and (log) urinary albumin excretion was determined by comparing linear regression lines. RESULTS: Microalbuminuria was significantly associated with the use of dihydropyridine calcium channel blockers (odds ratio: 1.76 [1.22-2.54]), but not with other antihypertensive drug groups. The linear regression line of the relation between blood pressure and (log) urinary albumin excretion was significantly steeper (P = 0.0047) for users of calcium channel blockers, but not for other antihypertensives, compared with subjects using no antihypertensive. Users of a combination of renin-angiotensin system inhibitors and diuretics however, had a less steep regression line (P = 0.037). CONCLUSIONS: This study suggests a disadvantageous effect of dihydropyridine calcium channel blockers on microalbuminuria compared with other antihypertensive drug groups. Thus, if microalbuminuria is causally related to an increased risk for cardiovascular morbidity and mortality, dihydropyridines do not seem to be agents of choice to lower blood pressure. Furthermore, the combination of renin-angiotensin system inhibition and diuretics seems to act synergistically.     

The relationship of white blood cell and platelet counts to cigarette smoking in adult Nigerians

This study was undertaken to examine the relationship between cigarette-smoking and total white blood cell count (wbcc) and platelet count (pc) in adult Nigerians. We also studied the relationship of the white blood cell and platelet counts to the duration of the smoking habit and number of cigarette smoked per day. Three hundred and fifty-two healthy male adults, aged 18-52 years, were studied. They were randomly allocated to two groups--176 smokers and 176 non-smokers. The smoking habit was assessed from a minimum period of 1 year and a minimum number of 5 cigarettes per day. Results revealed that platelet count was higher for the regular Nigerian smoker than for non-smoker. The difference between mean platelet counts for smokers and non-smokers was statistically significant (t = 2.64 p = 0.0046). Man WBC count in smokers was slightly higher than for non-smokers. However, unlike in the case of platelet counts, the mean difference in WBC count between smokers and non-smokers is not statistically significant (t = 0.07, p value = 0.9442). Similar studies based on white population has showed statistically significant increases in wbcc and pc in smokers.     

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers

Purpose

Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect.

Methods

Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (μ-Alb), beta-2-microglobulin (β₂-MG), retinol binding protein (RBP), N-acetyl-β-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey.

Results and conclusions

The median Cd-B, Cd-U, Pb-B were: 0.8 μg/l (IQR = 0.5, 1.2), 0.5 μg/g creatinine (IQR = 0.3, 0.8) and 158.5 μg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., μ-Alb and β2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.     

Excretion of volatile nitrosamines in a rural population in relation to food and drinking water consumption.

Urinary excretion of volatile nitrosamines was assessed in 59 non-smokers living in a rural county of Québec, Canada. Water and food intakes were measured by means of a 24-hour recall. Nitrates were analyzed in the tap water of all participants (geometric mean=2.0 mg nitrate-N/L) and dietary intakes of nitrate and vitamins C and E were estimated via a validated Canadian food database. Urine was collected over the same 24-hour period and analyzed for nitrates by hydrazine reduction and for volatile nitrosamines by gas-chromatography/mass spectrometry. N-Nitrosopiperidine (NPIP) was found in urine samples from 52 of the 59 subjects. Geometric mean of NPIP urinary excretion was 67 ng/day and maximum value was 1045 ng/day. No other volatile nitrosamine was detected. There was a correlation between urinary nitrate excretion and total nitrate intake (r=0.71, P < 0.001). However, no relationship was found between urinary NPIP excretion and either nitrate excretion, dietary or water nitrate intakes. NPIP excretion was significantly correlated to coffee intake (r=0.40, P=0.002) and this relation was not modified by vitamin intake. We conclude that nitrate intake is not related to nitrosamine excretion in this rural population. The influence of coffee consumption on NPIP excretion deserves further attention.     

The effect of smoking on nicotine metabolism in vivo in man

Nicotine and a basic metabolite, cotinine, were determined in the urine by gas-liquid chromatography after intravenous administration of (—)-nicotine hydrogen (+)-tartrate to groups of male and female smokers and non-smokers in whom the urine was maintained at an acid pH. The urinary recoveries of nicotine and cotinine from male smokers fell in two groups. One showed a lower recovery of both alkaloids than was seen with male non-smokers. The other showed a similar recovery of nicotine but more cotinine than the male non-smokers. Female smokers excreted less nicotine but more cotinine than female non-smokers. More nicotine but less cotinine was excreted by female non-smokers than by male non-smokers. The results show sex dependent metabolism of nicotine occurs in non-smoking humans and that smoking causes alterations in nicotine metabolism.