significantly interact with smoking and smokers with the variant genotypes were
20 times more likely to show evidence of p53 mutations than those with a CYP1B1
wild type genotype. As observed with tobacco smoking, significant gene–environment interaction was observed with variant genotypes of CYP1B1*2 and
CYP1B1*3 and tobacco chewing (Singh et al. 2008b). Studies also show a positive
correlation of variant genotypes of CYP2C19 with tobacco use which could be
possibly attributed to the lower ability of cases with genetic variations for
detoxifying the carcinogens generated by tobacco chewing or smoking (Sugimoto
et al. 2005). In contrast, CYP2D6 genotypes did not appear to interact significantly
with tobacco (Caporaso et al. 2001).
A study by Ruwali et al. (2009a) suggested that polymorphic CYP2E1 genotypes
interact with tobacco and increase the HNSCC risk with a greater increase in risk
observed in tobacco chewers which may be due to enhanced formation of
nitrosamines in tobacco chewing (Hecht and Hoffmann 1988). RsaI polymorphism
leads to a greater increase in transcription or enzyme activity than the DraI genotypes
due to which stronger association was observed with RsaI (Uematsu et al. 1994).
Soya et al. (2008) also reported an interaction between CYP2E1*6 (DraI) genotypes
and tobacco among South Indian tobacco users for upper aerodigestive tract cancers.
In addition, Harth et al. (2008) found an interaction of CYP1B1 (Leu432Val) and
CYP2E1 (À70G > T) genotypes among smokers indicating the relevance of combined genotypes with exposure to tobacco smoke in significantly enhancing the
HNSCC risk. In contrast, another study by Ruwali et al. (2009b) reported a reduction
for HNSCC risk in individuals who are exposed to risk factors such as tobacco
consumption (in the form of smoking and chewing) when compared to individuals
who are not exposed to such risk factors and carrying the variant genotypes of
CYP2A6. This reduction in HNSCC risk may possibly be attributed to a higher
number of cases with variant genotypes of CYP2A6 to be non-tobacco users than
tobacco users as variant alleles of CYP2A6 have been reported to reduce the risk of
tobacco consumption in the form of smoking and thus it is smoking that results in a
decreased HNSCC risk.
Among the phase II xenobiotic metabolizing enzymes, several studies have been
carried out to investigate the association between genetic variations in GSTs and
tobacco use. Studies have reported an association between null genotypes of
GSTM1 or GSTT1 and tobacco use in head and neck cancer patients (Sabitha
et al. 2008; Singh et al. 2008a; Ruwali et al. 2011). Smoking intensity also plays
an important role in deciding the outcome of the interaction. A significant association of GSTM1 null genotype with laryngeal cancer risk in light smokers was
observed (Jourenkova et al. 1998), while in some studies GSTM1 or GSTT1 null
genotype was found to be linked to upper aerodigestive tract (UADT), non-laryngeal
UADT or oral cancer risk in heavy smokers. Among the reasons for such an
interaction could be the higher sister chromatid exchange (SCE) and chromosomal
aberration levels in smokers with GSTM1 null genotype than GSTM1 positive
smokers (Nora 2004). In contrast to these studies, some of the earlier studies failed
to find any significant interaction of GST genotypes with tobacco-induced oral and
pharyngeal cancer (Jourenkova-Mironova et al. 1999). For GSTP1, inconsistent
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M. Ruwali and R. Shukla
20 times more likely to show evidence of p53 mutations than those with a CYP1B1
wild type genotype. As observed with tobacco smoking, significant gene–environment interaction was observed with variant genotypes of CYP1B1*2 and
CYP1B1*3 and tobacco chewing (Singh et al. 2008b). Studies also show a positive
correlation of variant genotypes of CYP2C19 with tobacco use which could be
possibly attributed to the lower ability of cases with genetic variations for
detoxifying the carcinogens generated by tobacco chewing or smoking (Sugimoto
et al. 2005). In contrast, CYP2D6 genotypes did not appear to interact significantly
with tobacco (Caporaso et al. 2001).
A study by Ruwali et al. (2009a) suggested that polymorphic CYP2E1 genotypes
interact with tobacco and increase the HNSCC risk with a greater increase in risk
observed in tobacco chewers which may be due to enhanced formation of
nitrosamines in tobacco chewing (Hecht and Hoffmann 1988). RsaI polymorphism
leads to a greater increase in transcription or enzyme activity than the DraI genotypes
due to which stronger association was observed with RsaI (Uematsu et al. 1994).
Soya et al. (2008) also reported an interaction between CYP2E1*6 (DraI) genotypes
and tobacco among South Indian tobacco users for upper aerodigestive tract cancers.
In addition, Harth et al. (2008) found an interaction of CYP1B1 (Leu432Val) and
CYP2E1 (À70G > T) genotypes among smokers indicating the relevance of combined genotypes with exposure to tobacco smoke in significantly enhancing the
HNSCC risk. In contrast, another study by Ruwali et al. (2009b) reported a reduction
for HNSCC risk in individuals who are exposed to risk factors such as tobacco
consumption (in the form of smoking and chewing) when compared to individuals
who are not exposed to such risk factors and carrying the variant genotypes of
CYP2A6. This reduction in HNSCC risk may possibly be attributed to a higher
number of cases with variant genotypes of CYP2A6 to be non-tobacco users than
tobacco users as variant alleles of CYP2A6 have been reported to reduce the risk of
tobacco consumption in the form of smoking and thus it is smoking that results in a
decreased HNSCC risk.
Among the phase II xenobiotic metabolizing enzymes, several studies have been
carried out to investigate the association between genetic variations in GSTs and
tobacco use. Studies have reported an association between null genotypes of
GSTM1 or GSTT1 and tobacco use in head and neck cancer patients (Sabitha
et al. 2008; Singh et al. 2008a; Ruwali et al. 2011). Smoking intensity also plays
an important role in deciding the outcome of the interaction. A significant association of GSTM1 null genotype with laryngeal cancer risk in light smokers was
observed (Jourenkova et al. 1998), while in some studies GSTM1 or GSTT1 null
genotype was found to be linked to upper aerodigestive tract (UADT), non-laryngeal
UADT or oral cancer risk in heavy smokers. Among the reasons for such an
interaction could be the higher sister chromatid exchange (SCE) and chromosomal
aberration levels in smokers with GSTM1 null genotype than GSTM1 positive
smokers (Nora 2004). In contrast to these studies, some of the earlier studies failed
to find any significant interaction of GST genotypes with tobacco-induced oral and
pharyngeal cancer (Jourenkova-Mironova et al. 1999). For GSTP1, inconsistent
226
M. Ruwali and R. Shukla