N-acetyltransferases

Many studies have examined the enzymes involved in the metabolism of amines and heterocyclic amines and suggested a significant relationship between polymorphisms of these enzymes and risk of CC⁽Reference Wang, Iwasaki and Haiman^12, Reference Ananthakrishnan, Du and Berndt¹³⁾. Heterocyclic amines are produced during cooking meat at high temperatures. N-acetyltransferases (NAT) are important enzymes in the metabolic activation of heterocyclic amines, which are found in two forms of NAT1 and NAT2. The rs1495741 polymorphism of NAT2 was strongly related to its activity and the GG, AG and AA genotypes are classified as enzymes with rapid, intermediate and slow activity, respectively. In people with the GG genotype of this polymorphism, there is a strong association between the consumption of red meat and the risk of CRC⁽Reference Wang, Iwasaki and Haiman^12–Reference Sørensen, Autrup and Olsen¹⁴⁾. Another study reported that cooking meat at a high temperature increased the risk of CC in people with NAT2 gene polymorphisms⁽Reference Lilla, Verla-Tebit and Risch¹⁵⁾. However, Barrett et al.⁽Reference Barrett, Smith and Waxman¹⁶⁾ provide no support for the hypothesis that those with the fast phenotype of NAT2 are at increased risk of CRC.

A study was conducted on 147 CRC patients (seventy-six women and ninety men); the cancer risk in women was found to be lower in the NAT intermediate activity phenotype, but this difference was not found in men. It has also been reported that in people with the GG genotype of NAT2 G857A, meat intake more than three times per week increased CRC risk⁽Reference Procopciuc, Osian and Iancu¹⁷⁾. However, some other studies failed to find any interaction between GG genotype, meat intake and CRC⁽Reference Da Silva, Felipe and de Lima^18–Reference Chan, Tranah and Giovannucci²⁰⁾. For example, Chan et al.⁽Reference Chan, Tranah and Giovannucci²⁰⁾ reported that there was no interaction between the amount of meat consumed with NAT1 and NAT2 and the risk of developing CRC. Overall, it can be concluded that NAT2 gene polymorphisms may have a role in CRC risk, especially in people with high meat intake.

Cyclo-oxygenases

Cyclo-oxygenases (COX) play a key role in converting arachidonic acid into prostaglandins. Red meat contains a substantial amount of arachidonic acid and most probably is involved in the inflammatory response and initiation of CC especially in people with a polymorphism in the COX-1 and COX-2 genes. This polymorphism occurs in the promoter region of the gene, resulting in a possible increase in gene expression with consequent elevation of levels of the COX-2 protein. Individuals who carry the polymorphisms that could affect the expressions of COX-2 are more susceptible to CC⁽Reference Shalaby, Nounou and Ms²¹⁾. There are two isoforms of the COX enzyme, COX-1 (or prostaglandin-endoperoxide synthase 1; PTGS1), that produces PG1, and COX-2 (or PTGS2), which produces PG2. The rs20417 (−765G > C) and rs5275 (8473T > C) polymorphisms of COX-2 play an important role in many cancers such as gastric cancer, prostate cancer and CRC. Some studies have also shown that the COX-2 rs1195AA genotype can also play a supportive role in the development of CRC. Makar et al.⁽Reference Makar, Poole and Resler²²⁾ showed that polymorphism rs20417 (−765G > C) in the COX-2 gene increases the risk of rectal cancer by up to two times higher than others. No significant relationship was reported between COX-1 gene polymorphisms and CRC in this study. In one meta-analysis study, there was a significant relationship between the COX-2 rs20417 polymorphism and the risk of CRC in an Asian population⁽Reference Peng, Yang and Lao²³⁾. Andersen et al.⁽Reference Andersen, Holst and Kopp²⁴⁾ suggested that the relationship between the COX-2 rs20417 polymorphism and the risk of CRC is influenced by dietary meat intake and COX-2 rs20417 risk allele carriers were at 8 % increased risk of CRC per 25 g/d higher red meat or processed meat intake. Generally, it can be concluded that COX-2 gene polymorphisms may have a role in CRC risk, especially in people with higher meat intake.

Cytochrome P450 2E1 and cytochrome P450 1A2

CRC is associated with environmental factors such as cigarette smoking, and consuming cooked meats and fish at high temperature. These factors result in the formation of carcinogenic compounds including polycyclic aromatic hydrocarbons, arylamines and heterocyclic amines. The cytochrome P450 (CYP) enzymes are critically important for the metabolism of these carcinogens by N oxidation⁽Reference Yoshida, Osawa and Kasahara²⁵⁾. CYP2E1 is an enzyme that plays a key role in the metabolism of nitrosamines and other carcinogens⁽Reference Hayashi, Watanabe and Kawajiri²⁶⁾. The RsaI polymorphism of CYP2E1 (C2 allele) is associated with an increased risk of CRC⁽Reference Hayashi, Watanabe and Kawajiri^26, Reference Shahriary, Galehdari and Jalali²⁷⁾. The RsaI polymorphism has been shown to affect its transcription level. The variant type of this polymorphic site can enhance transcription and increase the level of CYP2E1 enzymic activity in vitro ⁽Reference Le Marchand, Donlon and Seifried¹⁰⁾.

Some studies have also shown that individuals carrying a variant of the C2 allele have lower enzyme activity. In the Hawaiian population, it has been shown that the risk of CC has decreased in subjects carrying the RsaI C2 allele⁽Reference Shahriary, Galehdari and Jalali²⁷⁾. On the other hand, a study in China showed that homozygous individuals for the C2 allele were also more likely to develop CRC⁽Reference Van der Logt, Bergevoet and Roelofs²⁸⁾. Moreover, in some other studies, no relationship was observed between RsaI polymorphisms and the risk of CRC⁽Reference Gao, Takezaki and Wu²⁹⁾. Interestingly, Morita et al.⁽Reference Morita, Le Marchand and Kono³⁰⁾ showed that there is a significant relationship between red meat consumption and an increased risk of CC in the individuals carrying the RsaI C2 allele. However, another study reported that no significant relationship was observed between the the CYP2E1 RsaI polymorphism, red meat consumption and CC⁽Reference Silva, Felipe and Pimenta³¹⁾.

CYP1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body⁽Reference Wang, Joshi and Corral³²⁾. Some studies have shown that individuals carrying CYP1A2 polymorphisms are at higher risk of developing rectal cancer but not for CC⁽Reference Le Marchand, Wilkinson and Wilkens^33–Reference Cotterchio, Boucher and Manno³⁵⁾. In a case–control study on CYP1A2 polymorphisms, it was found that there was a significant relationship between the consumption of cooked meat at high temperature in −154A > C polymorphism carriers of CYP1A2 and the risk of CRC. Overall, it is possible that CYP2E1 and CYP1A2 gene polymorphisms may have a role in CRC risk, especially in people with higher meat intake.

Nucleotide excision repair pathway

The nucleotide excision repair (NER) pathway plays an important role in repairing damaged DNA. The NER pathway is a particularly important excision mechanism that removes DNA damage induced by UV light and environmental carcinogens⁽Reference Qiao, Spitz and Shen³⁶⁾. Xeroderma pigmentosum (XP) complementation group A (XPA), XP complementation group C (XPC) and XP complementation group D (XPD) are important enzymes in the NER pathway. There is a significant relationship between polymorphisms in XPA, XPC and XPD and a lower capacity of DNA repair. Numerous polymorphisms of NER genes have been identified and these changes individually or in combination may adversely affect NER fidelity, which could contribute to the risk of CRC. Four polymorphisms of these genes including A23G in XPA, Lys939Gln in XPC, and Lys751Gln and Asp312Asn in XPD have been identified that may have a significant relationship with the risk of CC⁽Reference Khan, Metter and Tarone³⁷⁾. For example, in a study conducted by Hansen et al.⁽Reference Hansen, Sørensen and Tjønneland³⁸⁾, a lower risk of cancer was reported in women with the Lys751Gln polymorphism of XPD. In homozygous individuals with the XPC Lys939Gln polymorphism, the risk of CC was increased by 3·7 times per 100 g/d increased intake of red meat. In the individuals carrying the wild-type allele, meat has no effect on CRC. No significant relationship was observed between other polymorphisms and CC.

Moreover, it was shown that people with a high consumption of red meat and XPD 312Asp and XPD 751Lys risk alleles have a higher chance of developing CRC than those with XPD 312Asn and XPD 751Gln alleles⁽Reference Joshi, Corral and Siegmund³⁹⁾. There is also a statistically significant interaction between Lys939Gln of XPC and A23G of XPA with red meat and processed meat intake and the risk of CC⁽Reference Hansen, Sørensen and Tjønneland^38, Reference Steck, Butler and Keku⁴⁰⁾. Overall, it can be concluding that higher meat intake may have a role in CRC risk, especially in people with polymorphisms in genes involved in the NER pathway.

DNA mismatch repair (mutator S)

A DNA mismatch repair protein, also known as mutator S (MutS), participates in the DNA mismatch repair system. In a study conducted on the polymorphisms of this gene, it was found that some gene polymorphisms were associated with an increased risk of CC. Processed meat intake could increase CC risk in people with the MutS polymorphism⁽Reference Berndt, Platz and Fallin⁴¹⁾. In another study, a significant relationship was observed between processed meat intake, the – polymorphism of the MutS gene and the risk of CC⁽Reference Laporte, Leguisamo and Kalil⁴²⁾. In general, it can be concluded that MutS polymorphisms may have a role in CRC risk, especially in people with higher processed meat intake.