Interindividual variation in carcinogen metabolism and bladder cancer risk.

Abstract

Epidemiological studies indicate that subjects of the genetically based slow acetylator phenotype may be at higher risk for bladder cancer than fast acetylators, particularly when they are exposed to carcinogenic arylamines: N-acetylation is a detoxification step in the metabolism of some arylamines. We describe two collaborative studies on tobacco smoking, in which markers of internal dose (arylamine-hemoglobin adducts) and markers of genetically based metabolic polymorphism have been coupled. In the first investigation, we found that hemoglobin adducts formed by mononuclear arylamines have high reciprocal correlation coefficients, as do adducts from binuclear arylamines. This tendency of adducts with structurally similar arylamines to correlate reciprocally explains a large proportion ofthe residual variance seen after controlling for smoking habits (number and type of cigarettes). In the second study, the concentration of 4-aminobiphenyl-hemoglobin adducts varied according to three independent determinants: number of cigarettes, type of tobacco (air or flue cured), and acetylator phenotype (slow and fast). The dose-response relationship between the amount of tobacco smoked and level of 4-aminobiphenyl-hemoglobin adducts in the slow acetylators (with an immediate steep increase of the adducts) was different from that in the fast acetylators (with a more regular increase). These findings from "molecular epidemiology" may contribute to an understanding of the role of metabolic polymorphism in human carcinogenesis.

Biomonitoring of urinary aromatic amines and arylamine hemoglobin adducts in exposed workers and nonexposed control persons

“…These results indicate that smoking habits, acetylator phenotype, and hemoglobin binding index may have important influences on the hemoglobin adduct levels of aromatic amines, at least those of aniline and 4-chloroaniline The determination of arylamine hemoglobin adducts seems to be a good parameter for monitoring aniline and 4-chloroaniline exposures at the workplace Additionally, the determination of aminodiphenyl hemoglobin adducts seems to be a good indicator of smoking habits; we found the highest mean adduct level in slow acetylating smokers and the lowest mean adduct level in both slow and fast acetylating nonsmokers (Tables 3, 4) This is in good agreement with the reports of other authors (e g , Bryant et al 1987Bryant et al , 1988Falter et al 1994 ;Vineis and Ronco 1992). It is interesting that 4-aminodiphenyl was only detected in a urine sample from one worker The reason for this could be the higher hemoglobin binding index of this substance in comparison to many other arylamines (Neumann 1988).…”

“…Significantly elevated mean hemoglobin adduct levels were found in slow acetylating workers for aniline and 4-chloroaniline (Table 2) This may not only be a consequence of higher exposure because a correlation was found between renal excretion and hemoglobin adduct levels only in fast acetylating workers for aniline Our results are in agreement with those of Lewalter and Korallus ( 1985), who described higher arylamine hemoglobin adduct levels in slow acetylators for comparable exposure levels in slow and fast acetylators Tannenbaum (according to Smith and Suk 1994), Vineis and Ronco ( 1992), and Yu et al ( 1994) found elevated 4-aminodiphenyl adducts in slow acetylators. In our study smoking slow acetylating workers had higher mean aniline and 4-chloro-aniline hemoglobin adduct levels,too (Table 3) There are small differences in the mean aniline and 4-chloroaniline hemoglobin adducts between slow acetylating smokers and nonsmokers and between the mean 4-chloroaniline hemoglobin adducts in fast acetylating smokers and nonsmokers (Tables 3, 4).…”

“…The detection of some arylamines in the urine of nonsmoking controls may be attributable to an environmental background level of arylamines-for example from combustion processes In addition, aromatic amines may enter the body from dyestuffs in cosmetics and clothing and from passive smoking. The occupationally exposed workers had higher levels of urinary aniline and 4-chloroaniline concentrations by comparison with the control group (Tables 1, 5); these two arylamines were the main exposure in all workers The mean urinary levels of aniline, p-toluidine, 4-chloro-o-toluidine, and 2-naphthylamine were higher in nonsmoking occupationally exposed workers than in nonsmoking controls By contrast, the mean urinary levels of o-toluidine, p-toluidine, 4-chloro-o-toluidine, and 4-methyl-1,3-phenylenediamine were higher in smoking controls than in smoking workers This may be due to different amounts of smoking in both groups These results indicate that smoking habits should be taken into account if the urinary excretion of arylamines is used in The use of hemoglobin adducts as an indicator of exposure to aromatic amines in biomonitoring has been recommended: hemoglobin adducts persist for the whole life of the erythrocytes, so that low chronic exposures can be detected (Bolt et al 1985 ;Lewalter und Korallus 1985Neumann 1984Neumann , 1991Skipper and Tannenbaum 1990) In our investigation three arylamine hemoglobin adducts were determined in occupationally exposed workers The mean 4-aminodiphenyl hemoglobin adduct level was higher in smokers than in nonsmokers, which may be an effect of the smoking habits Other studies have demonstrated that the hemoglobin adduct concentrations of o-toluidine, p-toluidine, 2-naphthylamine, and 3 and 4-aminodiphenyl are elevated in smokers Coghlin et al 1991 ;Falter et al 1994 ;Mac Lure et al 1989 ;Skipper et al 1988 ;Vineis and Ronco 1992 ;Yu et al 1994) The mean hemoglobin adduct levels of aniline and 4-chloroaniline were higher in the nonsmoking group of occupationally exposed workers than in the smoking workers (difference not significant). Unfortunately, we have no air concentrations of the aromatic amines at the workplace and no estimation of dermal contamination and uptake; therefore, we cannot correlate the results of our biomonitoring methods with individual exposure data We found good correlations between urinary concentrations and hemoglobin adduct levels in the case of aniline and absence of correlations in the case of 4-chloroaniline; this may be a consequence of the much higher hemoglobin binding index of chloroaniline (Neumann et al 1993 ;Sabbioni 1993).…”

DNA adduct burden and tobacco carcinogenesis

“…A series of earlier studies suggested that differences in carcinogen-adduct levels can correlate closely to differences in bladder cancer risks that are determined both by carcinogen exposure intensity and metabolic genotype (Vineis and Martone, 1996;Vineis and Ronco, 1992). Generally these studies support the idea that adduct levels correlate with smoking related risk, particularly those differences in risk associated with smoking black (air cured) versus blonde (flue cured) tobacco.…”

Using Biomarkers of Genetic Susceptibility to Enhance the Study of Cancer Etiology

“…The development of assays to measure these processes and their initial application in epidemiologic studies has been extensively reviewed (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Table 1 includes several examples of these processes, which can be studied at either the DNA level if the genetic basis of the polymorphism has been characterized, or at the phenotypic level using assays that reflect the function of either a single gene product (e.g., N-acetyltransferase, coded by NAT2) (4), or of several possible enzymes (e.g., DNA repair) (16 (17,18) and aflatoxin (19).…”