Alcohol, high blood pressure, and serum gamma-glutamyl transpeptidase level.

The influence of the level of serum gamma-glutamyl transpeptidase, a biological marker of alcohol consumption, on elevations of blood pressure and on the development of hypertension related to increases in alcohol consumption was determined in a cross-sectional study of 1,492 middle-aged male workers and in a subsequent 5-year follow-up study of 1,393 workers. Blood pressure levels, as well as the prevalence and incidence of hypertension, were higher in the subjects with serum gamma-glutamyl transpeptidase levels above 50 units/l than in those with normal levels. These differences were more marked in drinkers who consumed 30 ml or more of alcohol per day. Thus, elevated serum gamma-glutamyl transpeptidase activity may identify drinkers at higher risk for the development of alcohol-related hypertension.

HLA-A*24-B*07-DRB1*01 haplotype implicated with genetic disposition of peak bone mass in healthy young Japanese women.

HLA exhibits the most extensive polymorphism of any of the known human genes and is known as a genetic marker which allows genetic background of many diseases and physical phenomena. In this study, we, therefore, tried to investigate the regulation of HLA polymorphism and peak bone mass (PBM) in order to elucidate the genetic backgrounds of bone metabolism in young women. Subjects were 67 healthy young Japanese women (average age: 23.6 +/- 2.6 years, Body Mass Index (BMI): 19.9 +/- 2.0 who were randomly chosen. Allelic polymorphisms in HLA class I (HLA-A and -B) and HLA-class II (DRB1) were investigated by PCR-SSOP and PCR-SSP. Vitamin D Receptor (VDR) and Estrogen Receptor (ER) gene polymorphisms were also analyzed. Lifestyle factors, such as exercise and nutrition, were examined by questionnaire. Bone mineral density was examined using with Lunar DPX-L. Subjects who possessed HLA-B*07 had a significantly lower PBM than those without B*07 (p < 0.05). All subjects were divided into 3 groups according to HLA haplotypes linked with HLA-B*07, as follows: A*24(+/-)B*07(-)DRB1*01(+/-), A*24(+)B*07(+)DRB1*01(-), and A*24(+)B*07(+)DRB*01(+). There were no significant differences between these three groups in factors that affect bone metabolism, such as age, age at menarche, BMI, calcium intake, exercise habits, VDR or ER allele frequency. The HLA-A*24-B*07-DRB1*01 haplotype had a significantly lower Z score in the lumbar spine compared with subjects without this haplotype (p < 0.05). When the Z score was divided by values higher or lower than +1 or -1, all 3 subjects whose Z score was lower than -1.0 were found to have the HLA-A*24-B*07-DRB1*01 haptotype. A significant association between HLA-A*24-B*07-DRB1*01 and Z score < -1 was found (Yate's correction chi(2) = 10.82, p = 0.001, RR = 204). In conclusion, the HLA-A*24-B*07-DRB*01 haplotype can be considered a new genetic marker implicated with low PBM in healthy young Japanese women.

Polymorphism in ALDH2-genotype in Japanese men and the alcohol-blood pressure relationship.

Aldehyde dehydrogenase with a low Michaelis constant (Km), ALDH2, is a major enzyme involved in the conversion of acetaldehyde, a toxic metabolite of ethanol, into acetic acid in the liver. Inherited deficiency of ALDH2 activity is found in half of Japanese, and is characterized by "Oriental flushing" after alcohol consumption. The aim of the present study is to evaluate the influence of the genetic polymorphism in alcohol metabolism on the sensitivity to the pressor effect of alcohol. Genotypes of ALDH2 were determined in 403 middle-aged Japanese men using genomic DNA extracted from white blood cells. Two hundred and forty-three (60%) of the subjects were shown to be homozygotes for the normal ALDH2 gene, 25 (6%) of the subjects were homozygotes for the mutant ALDH2 gene, and the remaining 135 (33%) were heterozygotes. None of the homozygotes for the mutant gene drank enough to show the pressor effect of alcohol. Elevations of blood pressure associated with increasing alcohol consumption or with elevations of serum gamma-glutamyl transpeptide (GTP) level were not different between the other two ALDH2-genotypes. It can be concluded that polymorphism in the ALDH2-genotype found in Japanese men does not affect the individual sensitivity to the pressor effect of alcohol.

The relationship between serum gamma-glutamyl transpeptidase levels and hypertension: common in drinkers and nondrinkers.

A significant association between elevations of serum gamma-glutamyl transpeptidase (gamma-GTP) levels and those of blood pressure and hypertension has been reported separately in drinkers and nondrinkers. The aim of the present study is to evaluate whether the relationship between serum gamma-GTP and the prevalence of hypertension is the same or similar in both drinkers and nondrinkers. The study subjects comprised 4,920 male nondrinkers, 9,390 male daily drinkers, 8,081 female nondrinkers, and 278 female daily drinkers, who were aged 40 to 59 years. The prevalence of hypertension in the male and female daily drinkers was 1.5 and 1.3 times, respectively, higher than in the nondrinkers. Mean systolic blood pressure in the male and female drinkers was 4.4 and 3.1 mmHg, respectively, higher than in the nondrinkers. After adjusting for age, body mass index, and serum gamma-GTP levels, the differences in the prevalence of hypertension and the mean systolic blood pressure level between the drinkers and nondrinkers decreased to 1.2 times and 2.7 mmHg, respectively. Although these small differences remained statistically significant, the association between serum gamma-GTP and hypertension appears to be quite similar in both drinkers and nondrinkers, suggesting that hepatic steatosis may play a common, pathogenetic role in the development of hypertension.

Genetic differences in ethanol metabolizing enzymes and blood pressure in Japanese alcohol consumers.

Orientals have unique genetic polymorphisms in ethanol metabolizing enzymes, such as alcohol dehydrogenase-2 (ADH2), aldehyde dehydrogenase-2 (ALDH2) and cytochrome P450-2E1 (CYP2E1). Of the three studies conducted to clarify the influence of ALDH2 genotypes on sensitivity to the pressor effects of alcohol in Japanese, only one was suggested, though indirectly, higher sensitivity in drinkers having the genotype of inactive ALDH2. This discrepancy prompted us to determine ADH2, ALDH2 and CYP2E1 genotypes in the genomic DNA extracted from white blood cells of 855 healthy middle-aged Japanese men, and to analyse the associations with the alcohol-blood pressure (BP) relationship. No marked differences were found in the relationship among the genotypes of ALDH2, although the subjects with intact ALDH2 showed a slightly higher BP than those with inactive ALDH2 probably due to under-reporting of alcohol consumption in those with intact ALDH2 who could thus drink more. No significant influence of ADH2 genotypes was observed. A higher BP was noted in large volume alcohol consumers having c2/c2 genotype of CYP2E1. Multivariate regression analysis adjusting for the effects of age, body mass index and the volume of alcohol consumed, all of which are strong determinants of BP levels, showed only a marginal effect of c2 allele of CYP2E1 on diastolic BP elevations with increases in alcohol consumption. Thus it is concluded that the genetic polymorphisms in ethanol-metabolizing enzymes do not greatly influence the alcohol-BP relationship in Japanese men.

Relationship between serum gamma-glutamyl transpeptidase activity and blood pressure in middle-aged male and female non-drinkers.

Serum gamma-glutamyl transpeptidase (gamma-GTP) activity is a biological parameter for alcohol consumption. In our previous study, however, serum gamma-GTP levels seemed to correlate with blood pressure levels in both middle-aged male non-drinkers and drinkers. Therefore, the associations between gamma-GTP and BP were analysed more minutely in 385 male and 1126 female non-drinkers. The means of systolic (SBP) and diastolic (DBP) pressure in the males were significantly higher than those in the females, despite similar age and body mass index (BMI). The sex difference of BP disappeared after adjustment for serum gamma-GTP levels. The correlations between gamma-GTP and BP and the contributions of three variables, age, BMI, and gamma-GTP, to BP levels found in the non-drinkers in the present study were similar to those observed in the previous study on males including drinkers. These results suggest that common or possibly similar mechanisms which relate to the elevation of serum gamma-GTP activity are involved in the production of high BP both in non-drinking obese persons and in drinkers.

Relationship between serum gamma-glutamyl transpeptidase activity, blood pressure and alcohol consumption.

The associations among alcohol consumption, gamma-glutamyl transpeptidase (gamma-GTP) activity in serum and blood pressure (BP) were analysed in a cross-sectional study of 1,156 healthy male workers 35 to 59 years of age, consisting of 349 non-drinkers, 682 light-daily drinkers (consuming less than 58 ml of alcohol per day) and 125 heavy-daily drinkers consuming more. No marked elevation of BP with high alcohol consumption was seen in the present subjects. On the other hand, a linear elevation of BP together with an increase in serum gamma-GTP activity was found in subjects above 40 years of age. The BP levels corresponding to the three different drinking habits, non-drinkers, light drinkers and heavy drinkers, were similar to each other regarding gamma-GTP levels. The relationship between gamma-GTP and BP was shown, by multiple regression analysis, to be independent of age, obesity and the dose of alcohol consumed. The contribution to the rise in BP of the dose of alcohol consumed, in comparison with that of gamma-GTP, was negligible. Serum gamma-GTP activity is a useful indicator of the susceptibility to the pressor effect of alcohol.

Elevations of serum angiotensin-converting enzyme and gamma-glutamyl transpeptidase activities in hypertensive drinkers.

Serum angiotensin-converting enzyme (ACE) activity was measured in 70 middle-aged male drinkers with or without elevated serum gamma-glutamyl transpeptidase (gamma-GTP) activity and high BP. Serum ACE activity in hypertensive drinkers with elevated serum gamma-GTP was higher than that in drinkers, both normotensive and hypertensive, with normal serum gamma-GTP. Serum ACE levels were strongly correlated with alcohol consumption and serum gamma-GTP levels. Since the induction of ACE by alcohol in hepatic cells has been disputed, the coincident elevation of serum ACE and gamma-GTP activities in hypertensive drinkers may support the contention that the close association between gamma-GTP levels and BP found in drinkers is not mainly related to the induction of gamma-GTP in the hepatic cells, but related to the hepatic cell damage caused by alcohol.

Alcohol consumption, homeostasis model assessment indices and blood pressure in middle-aged healthy men.

A total of 1595 middle-aged healthy men consuming alcohol up to 120 ml per day and 538 without alcohol consumption were recruited from an occupational population, and their insulin resistance (IR) and beta-cell function (BC) were measured using the homeostasis model assessment (HOMA-IR and HOMA-BC), and the associations with alcohol consumption, blood pressure (BP), and serum gamma-glutamyltransferase (GGT) levels were analysed cross-sectionally. Both HOMA-IR and HOMA-BC were decreased with increasing alcohol consumption, but HOMA-BC corresponding to a level of HOMA-IR was 4-10 and 8-20% lower in drinkers consuming less than 60 ml of alcohol per day and those consuming more, respectively, than in nondrinkers, suggesting an altered fasting serum insulin-glucose relationship in alcohol consumers. Although BP was higher and HOMA-IR was lower in alcohol consumers than in nonconsumers, BP was higher at higher HOMA-IR irrespective of alcohol consumption. Elevations of serum GGT were positively associated with BP and HOMA-IR in both alcohol consumers and nonconsumers. Multiple regression analyses in the subjects showed that elevated serum GGT was an independent contributor to HOMA-IR elevations, and both serum GGT and HOMA-IR were significantly related to BP elevations after adjusting for alcohol consumption, age, body mass index, cigarette consumption, and physical activity at leisure. Although cross-sectional observations do not provide evidence of causal association, the results suggest that elevated serum GGT in alcohol consumers relates to elevations of IR and that the elevated insulin resistance relates, at least partly, to BP elevations in alcohol consumers.

Elevated cytosolic free calcium concentrations in platelets of hypertensive drinkers: a weak association with alcohol consumption.

Although the mechanisms of alcohol related hypertension remain unknown, it has been hypothesised that alcohol causes the accumulation of calcium ions (Ca2+) in vascular smooth muscle cells, resulting in the elevation of vascular tonus. To evaluate this contention, intra platelet free calcium concentrations (platelet [Ca2+]i) were determined in 20 young adult men, i.e. five each of hypertensive heavy drinkers, hypertensive light drinkers, normotensive heavy drinkers, and normotensive light drinkers. Platelet [Ca2+]i were higher in the ten hypertensives than in the ten normotensives, irrespective of alcohol consumption. The hypertensive drinkers also showed higher levels of serum gamma-glutamyl transpeptidase (gamma-GTP) and parathyroid hormone (PTH). Platelet [Ca2+]i in the total 20 subjects did not correlate with alcohol consumption, but correlated positively with serum gamma-GTP levels and SBP. These preliminary study results do not support the contention that Ca2+ accumulates in the vascular smooth muscle cells of humans as a result of chronic alcohol consumption. The significance of elevated platelet [Ca2+]i observed in the hypertensive heavy drinkers in the pathogenesis of alcohol related hypertension remains obscure.

Dose-response relationship between urinary cadmium and beta 2-microglobulin in a Japanese environmentally cadmium exposed population.

This study was carried out to test the dose-response relationship between urinary cadmium (Cd) and beta 2-microglobulin(beta 2-mg) and also to estimate the biological threshold value of urinary Cd concentration in inhabitants exposed to environmental Cd. Urinary Cd and beta 2-mg were measured in 3178 inhabitants over 50 years of age in the Cd-polluted Kakehashi River basin in Japan and 294 inhabitants in non-polluted areas. Urinary Cd and beta 2-mg were significantly higher in the Cd-exposed subjects than in the non-exposed subjects. Prevalence rates of beta 2-microglobulinuria(beta 2-mg-uria) increased proportionally with increasing urinary Cd concentrations and probit linear regression lines could be calculated between them. The urinary Cd concentration corresponding to the prevalence rates of beta 2-mg-uria among non-exposed subjects was calculated using the regression line, and values of 3.8-4.0 micrograms Cd/g creatinine for men and 3.8-4.1 micrograms Cd/g creatinine for women, respectively, were obtained. These values may be of use in establishing the biological threshold of urinary Cd concentration in environmentally Cd-exposed populations.

Significant increase of urinary mucoprotein in environmental-cadmium-exposed Japanese subjects.

Urinary mucoprotein (U-MP) was determined in 169 Japanese environmental-cadmium-exposed and 81 non-exposed subjects. Urinary total protein, albumin, beta 2-microglobulin (beta 2-MG), cadmium (Cd) and creatinine were also measured. Significant increases in U-MP and other proteins were found in the Cd-exposed subjects. Significant correlations between each protein were seen in the Cd-exposed and the total group of subjects. U-MP was highly correlated with urinary beta 2-MG and their correlation coefficient was the highest in the total group of subjects. beta 2-MG was the most sensitive indicator among them to detect Cd-induced renal dysfunction, although beta 2-MG is degraded in urine with a pH less than 5.5 U-MP is an acid-soluble protein. Therefore, U-MP is also available for studies on renal dysfunction caused by exposure to Cd, in conjunction with beta 2-MG.

Alpha 1-microglobulin in urine as an indicator of renal tubular damage caused by environmental cadmium exposure.

Alpha1-Microglobulin (alpha 1-m) was determined in the urine of both the cadmium-exposed and nonexposed subjects and was compared with those of other urinary parameters such as beta 2-microglobulin (beta 2-m), glucose, total protein or amino acids. Large amounts of alpha 1-m were detected in the urine of cadmium-exposed subjects. There were significant correlations between alpha 1-m and other urinary parameters. The sensitivity and specificity of both alpha 1-m and beta 2-m as indices of tubular dysfunction caused by cadmium was similar. It was concluded that alpha 1-m in urine seemed to be a useful indicator of renal tubular dysfunction caused by cadmium.

Serum bone-type alkaline phosphatase activity in women living in a cadmium-polluted area.

To clarify the significance of elevated serum total alkaline phosphatase activity (t-ALP) in persons exposed to environmental cadmium (Cd), the fraction of ALP originating from bone (b-ALP) was assayed using a wheat-germ agglutinin method in 23 men and 20 women in a Cd-polluted area who showed excessive urinary beta 2-microglobulin excretion, and in 21 men and 44 women in a non-polluted area, in addition to 7 patients with itai-itai disease. The fraction of b-ALP increased linearly with the increase in t-ALP in the women, irrespective of Cd-exposure. Elevations of both t-ALP and b-ALP in the Cd-exposed women, including inhabitants of the Cd-polluted area and patients with itai-itai disease, were found with decreases in serum calcium and bone density. It is concluded that elevated serum ALP levels found in Cd-exposed persons reflect the development of Cd-induced bone damage.

Urinary N-acetyl-beta-D-glucosaminidase and beta 2-microglobulin in 'itai-itai' disease.

N-acetyl-beta-D-glucosaminidase (NAG) activity in urine was measured in patients with 'itai-itai' disease, from chronically advanced cadmium poisoning. Elevation of NAG activity, however, was not so marked as that of beta 2-microglobulin (beta 2-MG) in the urine of patients and suspected patients. We conclude that the beta 2-MG test is more valuable than the NAG test for evaluating the severity of the renal tubular damage in chronically advanced cadmium (Cd) poisoning.

The relationship between itai-itai disease among inhabitants of the Jinzu River basin and cadmium in rice.

Women over 50 years of age in 32 cadmium(Cd)-polluted and 16 nonpolluted hamlets were studied. Itai-itai disease patients and proteinuria with glucosuria were used as indices of the effect of Cd on health. Unpolished rice samples were collected from 568 households in the same area and analyzed for Cd. The hamlet's average Cd concentration in rice was used as an index of Cd exposure. A close relationship between Cd exposure and health effects was found to exist when the women were classified according to their hamlet average rice-Cd concentrations. It is demonstrated that a dose-response relationship between Cd exposure and itai-itai disease exists.

Iron concentrations in liver and kidney of cadmium-exposed human subjects.

Iron (Fe) concentrations in liver and kidney of cadmium (Cd)-exposed people (11 Itai-Itai patients, 13 persons requiring observation and 4 Cd-exposed persons) were compared with those of nonexposed people. No significant difference in Fe levels in liver was observed between the groups. This fact indicates that anaemia in environmentally Cd-exposed people was not due to iron deficiency in contrast to findings in animal experiments.

alpha 1-Microglobulin determination in urine for the early detection of renal tubular dysfunctions caused by exposure to cadmium.

The determination of alpha 1-microglobulin (alpha 1-m) in urine was compared with that of beta 2-microglobulin (beta 2-m) for the detection of renal tubular dysfunctions caused by exposure to cadmium. alpha 1-m In urine is stable down to pH 4.5, whereas beta 2-m degrades below pH 5.5. The relationship between the urinary pH and alpha 1-m or beta 2-m in urine showed that alpha 1-m was independent of urinary pH, whereas beta 2-m-concentration decreased as urinary pH fell to a pH level below 6. Without a pH effect, alpha 1-m was highly correlated with beta 2-m in urine (N = 174, r = 0.96) from Cd-polluted subjects with renal dysfunctions. Due to the greater stability of alpha 1-m in urine, alpha 1-m seemed to be more advantageous than beta 2-m for the detection of renal tubular dysfunctions caused by Cd.

The renal handling of sodium and potassium in environmental cadmium-exposed subjects with renal dysfunction.

To clarify using clearance methods the renal handling of sodium and potassium in a population with environmental cadmium (Cd)-induced renal dysfunction, 76 Cd-exposed subjects (32 men and 44 women) and 36 non-exposed subjects (18 men and 18 women) were selected. Fractional excretions of potassium and beta 2-microglobulin were higher in the Cd-exposed subjects than in the non-exposed subjects, while the fractional excretion of sodium in the Cd-exposed subjects was equal to that of the non-exposed subjects. The urinary excretion rate of sodium was significantly lower in the Cd-exposed subjects than in the non-exposed subjects, while no significant difference was found in the urinary potassium excretion rate. Fractional excretion of sodium showed a significant correlation with age in all the subjects, while that of potassium significantly correlated with serum beta 2-microglobulin. These results indicate that increases in the fractional excretion of sodium or potassium do not directly signify increased urinary excretion of sodium or potassium in Cd-induced renal tubular dysfunction. The fractional excretion of potassium may be more affected by Cd-induced renal dysfunction, while that of sodium appears to be more related to age.

Sister-chromatid exchanges in the lymphocytes of people exposed to environmental cadmium.

Sister-chromatid exchanges (SCEs) were analyzed from peripheral lymphocyte cultures of 8 men and 16 women who had been exposed to environmental cadmium (Cd), and 6 controls. Average Cd concentrations in blood of the Cd-polluted group were 8.9 micrograms/l for men and 10.0 micrograms/l for women. These were no significant differences in SCE rates between the Cd-polluted and nonpolluted groups. There were no significant correlations between SCE rates and blood or urinary Cd concentrations. Cadmium alone may be an insignificant agent in producing chromosomal damage to peripheral blood lymphocytes.