Genetics_Essay FINAL - When Caffeine Kills P450 1A2...

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When Caffeine Kills P450 1A2 (CYP1A2) Mary Fernandes- 0964298 Sobika Easwaran- 0957771 Geerthana Jeyakumar-0958379 Tutorial: T09 T.A: Jessica Vanderploeg Due: March 17, 2011
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Several people incorporate a hot cup of coffee into their morning routine, for a burst of energy to take on another day of their busy lives. Some compounds in coffee, such as caffeic acid and chlorogenic acid, have antioxidant properties that may help protect against heart disease (Sohemy et al., 2007). Caffeine is a natural stimulant and is one of the many reasons why coffee is consumed. It has shown to increase the risk of myocardial infarctions in those individuals with certain mutations in their CYP1A2 gene (Sohemy et al., 2007). The CYP1A2 gene can also lead to cancer as it works with other proteins to biologically activate carcinogenic polycyclic aromatic hydrocarbons (PAHs) (Zhou et al., 2009). The CYP1A2 gene codes for a protein, that is a member of the cytochrome P450 superfamily of enzymes (Ou-Yang et al, 2000). The cytochrome P450 proteins are monooxygenases; these enzymes catalyze reactions involved in drug metabolism and synthesis of cholesterol, steroids, and lipids (Kot & Daniel, 2009). CYP1A2 activity can be influenced by a number of factors including hormones, body size, tobacco smoke, coffee intake, and cruciferous vegetables (Hong etl al, 2004). Mutations in the CYP1A2 gene, particularly the single nucleotide polymorphism (SNP) from adenine to cytosine at position 734 (1F allele), showed an increased risk of non-fatal myocardial infarctions among those homozygous for the allele (Yang et al., 2010). This mutation decreases the inducibilty of the CYP1A2 enzyme, leading to impaired caffeine metabolism, and as a result, those homozygous for the CYP1A2*1A allele (A/A), the wild type, are “rapid” caffeine metabolizers, while those homozygous for the *1F allele (F/F) are considered, “slow” metabolizers (Sohemy et al., 2007). 2
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CYP1A2 is located on chromosome 15q24.1 in humans, and has a close link with CYP1A1 by sharing a common 5-flanking region (Zhou et al, 2010). Both CYP1A1 and CYP1A2 are apart of the CYP1A family, and are positioned head-to-head, with a distance and of 23.3 kb apart. The CYP1A2 gene contains seven exons and six introns along a gene sequence that is approximately 7.8kb in length (Zhou et al., 2010). Once transcribed into RNA, the exons are spliced together. However, exon 1 and portions of exon 7 on the messenger RNA, form untranslated regions (UTRs) (Browning et al., 2010). The active region contains C458 and F451 amino acids in exon 7 and T321 in exon 4. The CYP1A2 gene is mainly expressed in human liver; its protein contributes to 13% of the total CYP protein in the liver. The CYP1A2 gene has one transcript, which is translated into a protein of 516 amino acid residues (Browning et al., 2010) with a molecular mass of 58, 294 Da. (Zhou, 2010). The CYP1A2 activity can be used to monitor the alterations of liver function in clinical practices (Ou-Yang et al, 2000). CYP1A2 P450 proteins are monooxygenases; a group of enzymes that
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Genetics_Essay FINAL - When Caffeine Kills P450 1A2...

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