Exposure Levels and Cytochrome P450 1A2 Activity, but not N-Acetyltransferase, Glutathione S-Transferase (GST) M1 and T1, Influence Urinary Mutagen Excretion in Smokers1
- Section of Occupational Health, Department of Environmental Medicine and Public Health, University of Padua, I-35128 Padua, Italy [S. P., E. C.], and Section of Hygiene and Occupational Medicine, Department of Clinic and Experimental Medicine, University of Ferrara, Ferrara, Italy [P. S., S. L., P. G.]
Abstract
We investigated the polymorphic enzymes cytochrome P450 1A2 (CYP1A2), N-acetyltransferase (NAT2), glutathione S-transferase (GST) M1 (GSTM1), and T1 (GSTT1) in relation to cigarette smoking-associated urinary mutagenicity detected on YG1024 Salmonella typhimurium strain with S9 mix in 97 smokers. In each subject, cigarette smoke intake was checked by analysis of urinary nicotine plus its metabolites. NAT2 and CYP1A2 phenotypes were determined by the molar ratio of urinary caffeine metabolites detected by high-performance liquid chromatography, and GSTT1 and GSTM1 genotypes were determined by PCR. An increase in urinary mutagenicity was significantly related to levels of exposure to cigarette smoke and CYP1A2 N-hydroxylation activity (linear multiple regression analysis t = 4.51 and P < 0.001 and t = 3.09 and P = 0.003; F = 6.31, P < 0.001). Urinary mutagenicity was significantly higher in CYP1A2 extensive metabolizer smokers (n = 49) than in CYP1A2 poor metabolizer ones (n = 48; 2176 ± 1525 versus 1384 ± 1206 revertants/mmol creatinine, Mann-Whitney U-test, z = 2.65, P < 0.001). The highest mutagenic activity was seen in subjects CYP1A2 extensive metabolizer/NAT2 slow acetylators (n = 29) with respect to the other phenotype combinations (n = 68; 2392 ± 1660 versus 1525 ± 1238 revertants/mmol creatinine, Mann-Whitney U-test, z = 2.37, P = 0.017). NAT2 acetylation activity was slightly but inversely related to urinary mutagenicity, and the association was not significant. No effect of GSTM1 and GSTT1 genotypes in lowering (detoxifying) urinary mutagens was found. The significant enhancement of urinary mutagenicity associated with increased CYP1A2 activity, as already seen for diet-caused urinary mutagenicity, allows for many analogies between the process of mutagen formation derived from cooked meat and that from cigarette smoke condensate. In conclusion, the intensity of tobacco smoke exposure, modulated by CYP1A2 activity, is the major determinant of mutagenic urine among smokers, whereas GSTM1 and GSTT1 genotypes have no influence on this biomarker. This study suggests that CYP1A2 should definitely be determined in future studies involving urinary mutagenicity in cases in which smoking is a factor.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by a MURST 1999 grant.
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↵2 To whom requests for reprints should be addressed, at Section of Occupational Health, Department of Environmental Medicine and Public Health, University of Padua, Via Giustiniani 2, I-35128 Padua, Italy. Phone: 39-049-8216600; Fax: 39-049-8212542; E-mail: erminio.clonfero{at}unipd.it
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↵3 The abbreviations used are: CSC, cigarette smoke condensate; AA, aromatic amine; AFMU, 5-acetylamino-6-formyl-amino-3-methyluracile; CYP1A2, cytochrome P450 1A2; GST, glutathione S-transferase; HAA, heterocyclic aromatic amine; PAH, polycyclic aromatic hydrocarbon; NAT2, N-acetyltransferase; 17U, 1,7-dimethyluric acid; 1U, 1-methyluric acid; 1X, 1-methylxanthine; EM, extensive metabolizer; PM, poor metabolizer; CV, coefficient of variation.
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- Accepted May 29, 1902.
- Received December 26, 1901.
- Revision received May 15, 1902.
