The blood flows in the circulatory system of the human body. The circulatory system is made up of arteries (blood vessels), veins and capillaries. The blood keeps on running in the circulatory system because of continuous pumping by the heart. The oxygenated blood passes through the arteries throughout the body. But as the arteries moves far away from the heart, they appear smaller in size and ultimately turn into capillaries. They constitute the smallest blood vessels of the circulatory system. The capillary blood supply oxygen and absorb CO2 along with other waste gases from the cells. The capillaries are linked to every smallest veins of the body. The veins become bigger in size as they carry the deoxygenated blood back to the heart. Blood passes through the right part of the heart and moves to lungs where it loses carbon dioxide and other gases and absorbs oxygen again. Then it passes through the left part of the heart where it is pumped back to the body. The blood always circulates in the body in same direction. Many substances like oxygen, carbon dioxide are carried with the blood. During blood circulation through digestive system, it collects digested food products and later carries them to the liver where it is to be used or stored.
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Fig.1: Diagram showing circulatory system of humans.
The circulation of the blood also help to explain that why some cancers always spread to a same place. Cancer in colon often spreads to the liver since blood circulates from the colon through the liver on returning to the heart. For example, if there is cancer in colon and some cancer cells break-off into the circulation, they will stick to the liver as the blood passes through it. Then it leads to growth of a secondary cancer.
Fig.2: Diagram showing a cancer cell struck in a small blood capillary.
What is present in blood?
The normal colour of blood is red but, if it is left in a test tube for a while it gets separated into plasma and blood cells in the form of a solid layer.
Fig.3: Diagram of blood sample.
The blood contains fifty five percent plasma and forty five percent of cells. The Plasma is constituted by water, proteins and other dissolved chemicals. Blood mainly contains three main cells namely Red blood cells (WBCs), White blood cells (RBCs) and blood platelets.
Plasma cell is the liquid part of blood that transports dissolved substances within the body circulatory system and defends it against disease. Plasma contains a variety of constituents like antibodies, antitoxins, amino acids, carbonate ions, fibrinogen, glucose, hormones, hydrogen, lipoproteins, mineral salts and phospholipids.
Function of plasma in blood:
The blood plasma helps in the transportation of vitamins, hormones, CO2 and urea. It also plays an important role in defence mechanism of the host as it contains antibodies and antitoxins. Plasma is involved in the process of forming blood clots.
White blood cells
White blood cells are of different types and of different amounts in the blood. They all are responsible in immune responses by the body. They help in responding to infection that occurs in the body which may be caused by a foreign particle. These blood cells are generated in short time and have a short life span (few hours to some days). The normal WBC count is about 4,000 to 11,000 in a cubic mm of blood. Most frequent of the white blood cells are neutrophils (leucocytes). Their number is about 2,000 and 7,500 per cubic mm of blood. They help in fighting infection. Next most frequent are the lymphocytes. Their number varies from 1,300 to 4,000 in a cubic mm of blood. They are concerned in making antibodies. The remaining WBCs constitute lesser amounts in the blood. They are between:
40 and 400 of eosinophils.
0 and 100 of basophils.
200 and 800 of monocytes.
Fig.1.4: Diagram shows parts of the body where blood cells are made.
Red blood cells
Red blood cells are red in colour due to the presence of a pigment named haemoglobin. Every cubic mm of blood contains 4 to 5 million red blood cells. Their life expectancy is 120 days. A red blood cell attaches to an oxygen molecule and carries it during circulation within the tissues. When RBC's come across any area where the oxygen is needed, they supply it and take up carbon dioxide which is carried back to the lungs. Shortage of RBC's is called anaemia. Role of the RBC's in carrying oxygen explains why every anaemic people usually feel breathlessness.
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Platelets are a bit bigger cells present in blood usually called as megakaryocytes. A cubic mm of blood contains 150,000 to 440,000 platelets. The blood platelets are involved in blood clotting mechanism. Their mechanism is that they all clump together to form a plug where bleeding occurs in the body. Later they release other chemicals that help blood to clot which repairs the damaged blood vessel.
Formation blood cells
Blood stem cells are the precursors of different blood cell types. These Stem cells are present within the red bone marrow of the bone. Their production is also observed mainly in skull, rib bones, breast bone, pelvis and spine. Stem cells differentiate into myeloid and lymphoid stem cells. Myeloid stem cells produce RBCs, WBCs and blood platelets. Stem cell differentiation is as shown the figure below. The lymphoid stem cells divide into lymphoblast producing plasma cells, T lymphocytes, natural killer cells and B lymphocytes.
Fig.5: Diagram of various cell differentiations.
Blood cancer refers to a malignant condition in bone marrow, blood or even the lymph.
Blood cancer can be classified into
It is termed as malignancy of cells in blood and starts in tissues that form blood. During leukemia, the bone marrow produces abnormal white blood cells and the cells are termed as leukemia cells. Unlike normal blood cells, the properties of the leukemia cells get altered. They may over count the normal white, red blood cells, and also platelets. It creates problem for the normal blood cells to perform their work. They are of two types:
Chronic leukemia: This leukemia cell performs some work of normal white blood cells as they show no symptoms at the beginning. Chronic leukemia gets worse as the leukemia cells multiply. Symptoms seen are swollen lymph nodes or any infection.
Acute leukemia: This leukemia cell can't perform any work of normal white blood cells. This type of cells multiplies very rapidly and acute leukemia generally worsens quickly.
Myelogenous Leukemia: They develop from myeloid stem cells. This disease can either be chronic or acute, and termed as chronic myelogenous leukemia, or acute myelogenous leukemia.
Lymphocytic Leukemia: They develop from cells called lymphoblast or lymphocytes in the blood bone marrow. This disease too can be acute or chronic, and termed as chronic lymphocytic leukemia, or acute lymphocytic leukemia.
The malignant tumors of the lymph system are termed as lymphoma. In this type of cancer the cells involved are the lymphocytes of the immune system. Lymphoma represents 35 different subtypes of cancers of lymphocytes. It is a malignant transformation of B/T cells, and their respective subtypes. When abnormal cells multiply they get collected in one or more lymph nodes or in lymph tissues, e.g. spleen. During lymphoma they travel from one lymph node to the others and also to remote organs through the lymphatic system. They fall in two major categories:
Hodgkin's lymphoma: It occurs from a specific abnormal B lymphocyte lineage. They are of five subtypes. They are microscopically distinct and typing is based on the microscopic differences as well as extent of the occurrence of disease.
Non-Hodgkin's lymphomas: It occurs from either abnormal B or T cells. 30 subtypes of non-Hodgkin's lymphoma have been identified. They look similar but are functionally different.
It is malignancy occurring in the plasma cells. Myeloma occurs due to abnormal production of plasma cell. The abnormal cell divides to make multiple copies of it and this process goes on and on. These abnormal plasma cells are termed as myeloma cells. These cells get accumulated in bone marrow and begin damaging the solid part of the bone marrow. When myeloma cells get distributed in several regions of the bones, the disease then termed as "multiple myeloma".
These cells are responsible of producing antibodies in bone marrow. As a group they are termed as Hematological malignancies.
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Exposure to radiation.
Exposure to chemicals.
Human T-cell Leukaemia Virus.
Person becomes weak.
Recurrent bleeding of the gums and nose.
Fever that is recurrent.
Profuse sweating in night.
Loss in weight.
Enlargement in Lymph gland.
Swelling in the abdomen.
Blurry vision and frequent pain in the head.
Formation of dark spots and rashes.
Symptoms of leukemia are anaemia, continuing infections, pain in the joints, abdomen and trouble in breathing. In lymphoma, the symptoms depend on location and size of the tumour. Initial symptoms are swelling in the underarm, groin or neck. Multiple myeloma is characterized by pain in the bone due to damage caused by plasma cells.
Smoking effects on the Circulatory System
Smoking results in a rise in blood pressure and heart rate. Contraction in blood vessels of skin results in drop of temperature of the skin. Less oxygen carried by the blood. Cause sticky blood formation which is more prone to clotting. Also cause damage to the lining of the arteries which is thought to be a contributing factor to atherosclerosis or fatty deposits on the artery walls. Blood flow reduced to extremities like fingers and toes. Increase in risk of stroke and heart attack due to blockage of the blood supply. CO from cigarette smoke damages the inner vessel walls making prone to fat and plaque deposition. Nicotine acts as adjuvant as each time it attacks our brain it activate the stress defence mechanism which in turn releases the stored fats into our blood stream that stick to the vessel walls damaged by CO. It is seen that nicotine stimulate vascularisation or formation of new blood vessels within existing vessels accelerating narrowing, clogging and constriction of blood vessels. Unnecessary coronary and carotid vessel constriction leads to heart attack and stroke.
Smoking Induced Leukemia
Cigarette smoking is related with an increased risk of leukemia. Benzene is a recognized leukemogen which is present in cigarette smoke. Smokers are two times more expected to develop leukemia than non-smokers. It is still uncertain about the doses of benzene that will create a risk for leukemia. Benzene is present in mainstream cigarette smoke (conc. of approx 45 Âµg/cigarette) and sidestream smoke at concentrations about 10 times higher than mainstream. Average cigarette smokers inhale 6-10 times the benzene inhaled by the average non-smoker. Benzene induces leukemia in humans with working exposures. The strongest relationship of benzene is with acute myeloid leukemia, although effects on former types of leukemia have not been ruled out.
Lung Cancer and Tumour Vasculature
In an article of tobacco related disease research program (TRDRP) a plan for vascular targeting strategy has been established where the difference of protein expression in endothelial cells of normal tissue vasculature and cancerous tissue vasculature has been exploited. 2-D gel electrophoresis results of normal tissue vasculature endothelial proteins were compared with the tumour vasculature endothelial proteins revealed several well separated protein spots in tumour vasculature endothelial protein analysis. 5 new spots (TE: 1-5) appeared in tumour vasculature endothelial proteins that appear to be lung tumour induced. Antibodies used against TE-3 revealed it to be lung tumour specific by western blot analysis, tissue immunostaining and in vivo targeting. Monoclonal antibodies (m-Abs) were developed and one of them - TC004 appears to be lung tumour specific. Cycloxygenase - 2 (COX-2) is an enzyme, found in lung cancer cells responsible for suppressing patient's immune system, thus contributing to the growth of lung cancer. The next objective is to find out how COX-2 regulates the progression of tumour growth in lung cancer, which can form the basis of designing COX-2 inhibitors in prevention and therapy for lung cancer.
Genetic Level Understanding Of Smoking Induced Blood And Circulatory System Cancer.
The risk of acute myeloid leukemia (AML) increased two fold and acute lymphocytic leukemia (ALL) increased threefold due to smoking. Exposure to cigarette smoke may result in genetic changes that are random hence effecting the normal stem cell proliferation.
Dale, P. S., David, L. S., James, R. A., Frederick, R. D., Dianne, A., Robert, J. M., Richard T. S., Raymond, B. W., Joseph O. M., Charles, A. S., Doris, H. Wurster-Hill., Mclntyre, O. Ross. And Clara, D. B. (1993). "Cigarette Smoking and Risk of Acute Leukemia: Associations With Morphology and Cytogenetic Abnormalities in Bone Marrow". Journal of the National Cancer Institute. 85, 24.
Many DNA adducts have the potential to cause mutations and also has a possible link between DNA adducts and oncogene mutations induced by PAH in white blood cells. Mutations in codons 12, 13 or 61 of one of the three genes, H-ras, K-ras, and N-ras, have been reported to convert these genes into active oncogenes. H-ras protooncogenes have been chemically mutated in codon 12 in vitro by benzo (a) pyrene-diolepoxide (BPDE). Ki-ras codon 12 mutations and the majority of the mutations were G-T transitions of the second G of codon 12.
Maanen, J.M.S., Maas, L.M., Hageman, G., Kleinjans, J.C.S. and Agen, B., (1994) "DNA Adduct and Mutation Analysis in White Blood Cells of Smokers and Non-smokers, Dept of Health Risk Analysis and Toxicology". Environmental and Molecular Mutagenesis. 24, 46-50.
Molecular analysis of hprt c-DNA from 6-thioguanine-resistant T-lymphocytes which is cloned from smoking and non-smoking adult donors showed that 35% mutants to be defective during splicing of hprt mRNA. There was also loss of exon 4 which was more frequent than the other exons. The splice regulating sequences of this exon are both larger than other exons or are prone to mutation. Defective splicing is caused by base pair substitutions or small.
Rossi, A. M., Tates, A. D., Zeeland, A. V. A. and Vrieling, H. (1992) "Molecular analysis of mutations affecting hprt mRNA splicing in human T-lymphocytes in vivo". Environmental and Molecular Mutagenesis.19(1), 7-13.
Lung cancer risk increases 20-fold due smoking. There is also an increase in risk of developing many types of diseases like COPD and cancers. CTCF was down regulated in the high cotinine group. Mutations of this gene have been associated with a variety of cancers. Moreover, CTCF plays an important role in the regulation and differentiation of human myeloid leukemia cells, adding another possible underlying mechanism of leukemiagenesis in tobacco users. The pro-apoptotic genes C1D, MTCBP-1, CTCF, IKIP, MA and YWHAQ were all significantly down regulated in the high cotinine group.
Charles, P. C., Alder, B. D., Hilliard, E. G., Schisler, J. C., Lineberger, R. E., Parker, J. S., Mapara, S., Wu, S. S., Portbury, A., Patterson, C and Stouffer, G. A.(2008). "Tobacco use induces anti-apoptotic, proliferative patterns of gene expression in circulating leukocytes of Caucasian males". BMC Medical Genomics. 1, 38.
The influence of polymorphic glutathione S-transferases Î¼ (GSTM1) and Î¸ (GSTT1) on the rate of chromosome aberrations (CA) in peripheral lymphocytes of 30 pesticide-exposed floriculturists and 32 control subjects was studied. Among cigarette smokers, a statistically significant (p=0.026) increase in baseline CA frequencies was observed in subjects with a homozygous deletion of the GSTM1 gene (GSTM1 null, n=36) in comparison with those having at least one copy of the gene (GSTM1 positive, n=26). In addition, the few individuals (n=5) deficient for both GSTM1 and GSTT1 showed significantly higher (p=0.012) CA counts than GSTM1 positive GSTT1 nulls.
Scarpato, R., Hirvonen, A., Migliore, L., Falck, G. and Norppa, H.(1997). "Influence of GSTM1 and GSTT1 polymorphism on the frequency of the chromosome aberrations in lymphocytes of smokers and pesticide-exposed greenhouse workers". Mutation Research/Genetic Toxicology and Environmental Mutagenes. 389 (2-3), 227-235.
2mg of benzene is produced from smoking every pack of cigarettes. Benzene has been found to induce leukemia. CYPE1 metabolizes benzeneïƒ benzene oxideïƒ phenolïƒ di & tri hydroxybenzenes. Therefore this enzyme has an important role in creating toxicity. Glutathione transferases on the other hand help in detoxification by converting benzene oxide to phenylmercapturic acid. NQO1 also helps in detoxification. A mutation of C->T at position 609 makes a person prone to toxicity.
Smith, M. T. and Zhang, L. (1998). "Biomarkers of Leukemia Risk: Benzene as a model, Environmental Health perspectives". Environ Health Perspect. 106(4), 937-946.
The relationship of genetic polymorphisms to carcinogenicity has been extensively studied for phase I enzymes on cytochrome P450 lAl (CYP1A1) and cytochrome P450 2D6 (CYP2D6) gene. And phase II enzymes on glutathione S-transferase MI (GSTMI) and N-acetyl transferase 2 (NAT2) genes. The high activity of GSTM1 to convert PAHs to epoxide metabolites is thought to be particularly important. GSTT1 catalyzes the detoxification of the mono-halomethanes. Subjects that are homozygous for the NQOI 609C-T mutation has a 7.6-fold increased risk for benzene poisoning.
Sram, R. J. (1998). "Effect of Glutathione S-transferase M1 Polymorphisms on biomarkers of exposure and effects". Environmental Health Perspectives. 106(1), 231-239.
Advances in both biological and epidemiological fields proved rather consistent associations between cancer risk and polymorphisms, including NAD(P)H quinone oxidoreductase 1 gene (NQO1), C609T, (Pro187Ser), glutathione S-transferase M1 (GSTM1), and glutathione S-transferase T1 (GSTT1). GSTT1 null genotype and Paraoxanose (PON1) BB genotype are associated with risk of non-Hodgkin's disease and Multiple Myeloma in Caucasians.
Hishida, A., Terakura, S., Emi, N., Yamamoto, K., Murata, M., Nishio, K., Sekido, Y., Niwa, T., Hamajima, N. and Naoe, T. (2002) "GSTT1 and GSTM1 deletions, NQO1 C609T polymorphism and risk of chronic myelogenous Leukemia in Japanese, Asian Pacific Journal of Cancer Prevention". Asian Pac J Cancer Prev. 6(3), 251-255.
Six GST isoenzyme classes have been identified. GSTM1 and GSTT1, located on the chromosomes 1q13.3 and 22q11.2 have functional polymorphism in the form of homozygous deletion of either or both genes leading to absence of their phenotypic enzyme activities.
Mossallal, G. I., Hamid, T. M. A. and Sarma, M. A.(2006). "Glutathione S-Transferase GSTM1 and GSTT1 polymorphisms in adult Acute Myeloid Leukemia; Its impact on toxicity and response to chemotherapy". Journal of Egyptian Nat. Cancer Inst. 18(3), 264-273.
GSTP1 is the major enzyme involved in the detoxification of the cigarette smoke carcinogen, mainly as benzo[a]pyrene diol epoxide and other toxic constituents (acrolein). The GSTP1 (Ile105Val) single nucleotide polymorphism resulted from A135G transition in exon 5.
Suneetha, K. J., Nancy, K. N., Rajalekshmy. K. R., Sagar, T. G. and Rajkumar, T. (2008). "Role of GSTM1 (Present/Null) and GSTP1 (Ile105Val) Polymorphism in susceptibility to Acute Lymphoblastic Leukemia among the South Indian population". Asian Pacific J Cancer. 9(4), 733-736.
NQO1 activity is a well-authenticated component of pathways for mutagen and carcinogen activation, an inducible enzyme and is increased (by cigarette smoking). The base pair substitution in codon 187 of NQO1 were linked with a functional decrease in amount of quinone reductase activity and those individuals would have an increased susceptibility to the genotoxic and leukemogenic effects of cytotoxic therapy. Benzene-induced hematotoxicity associated the 609C=T mutation of NQO1. It is sensible to assume that mechanism of leukemogenesis between these two categories which is loss or deletion of 5 or 7 and balanced translocation is substantially different.
Larson, R. A., Wang, Y., Banerjee, M., Wiemels, J., Hartford, C., Beau, M.M.L. and Smith, M. T. (1999). "Prevalence of the inactivating 609 Cïƒ T polymorphism in the NAD (P) H: Quinone Oxidoreductase (NQO1) gene in patients with primary and theraphy-related Myeloid Leukemia". Blood. 94(2), 803-807.
PON1 was found to be associated with non-Hodgkin's lymphoma and multiple myeloma cancer. SNPs found in this gene were T->A in exon 3 resulting in a leucine to methionine change in expression. An A->G polymorphism in exon 6 caused a glutamine to arginine substitution.
Lurie, G., Wilkens, L. R., Thompson, P. J., McDuffie, K. E., Carney, M. E., Terada, K. Y. and Goodman, M. T. (2008). "Genetic Polymorphisms in the Paraoxonase 1 Gene and Risk of Ovarian Epithelial Carcinoma". Cancer Epidemiol Biomarkers Prev. 17(8), 2070-2077.
Hung et al. previously observed that the XRCC1 399 (Gln-Gln) genotyping was linked with increased risk of tobacco-related cancers among light smokers, but decreased risk among heavy smokers. The metabolic genotypes CYP3A5 (A-44-G) and GSTP1 (Ile105Val) and DNA-repair genotypes XRCC1 (Arg399Gln, Arg194Trp, T-77-C) and XPD (Asp312Asn, Lys751Gln) were identified by polymerase chain reaction. The X-ray cross-complementing group 1 (XRCC1) gene product coordinates the actions of DNA polymerase Î², DNA ligase III Î±, and poly (ADP-ribose) polymerase, APE1, polynucleotide kinase/phosphatase, and 8-oxoguanine DNA glycosylase. The Arg399Gln (exon 10, base Gâ†’A) is located in the region of the BRCT-I interaction domain of XRCC1 with poly (ADP-ribose) polymerase, and the Arg194Trp (exon 6, base Câ†’T) occurs in the identified proliferating cell nuclear antigen (PCNA) binding region. Although measurement of persistence of DNA adducts, increased p53 mutations, and prolonged cell cycle delay has been used to show the association of 399Gln and 194Trp variant alleles with some DNA repair phenotypes. The xeroderma pigmentosum group D (XPD) protein, a subunit of transcription factor IIH, is an evolutionarily conserved 5'â†’3' helicase that unwinds the DNA in the region of DNA damage. Single nucleotide polymorphisms (SNP) in the XPD gene have been studied. XPD Asp321Asn in exon 10 causes an amino acid substitution in a conserved region of XPD. XPDLys751Gln in exon 23 also causes an amino acid substitution in the C-terminal part of the protein.
Wong, R. H., Chang, S. Y., Ho, S. W., Huang, P. L., Liu, Y. J., Chen, Y. C., Yeh, Y. H. and Lee, H. S. (2008). "Polymorphisms in metabolic GSTP1 and DNA-repair XRCC1 genes with an increased risk of DNA damage in pesticide-exposed fruit growers", Mutation Research. 654. 168-175.
Methylenetetrahydrofolate reductases (MTHFR) direct 5, 10-methylenetetrahydrofolate toward methionine synthesis at the rate of DNA synthesis. Two MTHFR polymorphisms, C677T and A1298C, have been linked with less enzyme activity and C677T with altered distribution of intracellular folate metabolites. Primary function of folate is transporter for single carbon fragments in the change of homocysteine to methionine and purine and prymidine synthesis. The gene for MTHFR enzyme is found at the end of the short arm of chromosome 1 (1p36.3). The C677T polymorphism occurs in exon 4 and results in alaïƒ val at codon 222. A second MTHFR polymorphism (A1298C) in exon 7, results in a gluïƒ ala at codon 429. The polymorphism identified at 1317bp is a Tïƒ C substitution without altering amino acid sequence. Rady et al. described a Gïƒ T substitution at 1793bp, resulting in an argïƒ glu at codon 594.
Robien, K and Ulrich, C.M. (2003). "5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview". American Journal of Epidemiology. 157(7), 571-582.
Non-Hodgkin lymphoma subtype showed steady association between cigarette smoking and non-Hodgkin lymphoma was observed among follicular lymphomas. Cigarette smoking may increase the risk of developing follicular lymphoma with no affect in risk for other non-Hodgkin lymphoma subtypes. But cigarette smoking increases risk of non-Hodgkin lymphoma through direct carcinogenic effects as seen for t (14; 18) translocation. This somatic mutation joins the immunoglobulin heavy chain gene on chromosome 14 with the bcl-2 gene on chromosome 8, resulting in increased production of the bcl-2 protein that inhibits apoptosis. Direct effect of carcinogenic compounds in cigarette may increase the percentage of t (14; 18) translocation in lymphoma cells, since this mutation occurs more frequently among heavy smokers. It is reported that non-significant 70% increased risk of t (14; 18) positive non-Hodgkin lymphoma, but not t(14; 18)negative non-Hodgkin lymphoma, among cigarette smokers. It is estimated that t (14; 18) translocation occurs in female 85% of follicular lymphomas and 30% of diffuse lymphomas.
Morton, L. M., Hartge, P., Holford, T. R., Holly, E. A., Chiu, B. C. H., Vineis, P., Stagnaro, E., Willett, E. V., Franceschi, S., Vecchia, C. L., Hughes, A. M., Cozen, W., Davis, S., Severson, R. K., Bernstein, L., Mayne, S. T., Dee, F. R., Cerhan, J. R., and Zheng, T. (2005). "Cigarette Smoking and Risk of Non-Hodgkin Lymphoma: A Pooled Analysis from the International Lymphoma Epidemiology Consortium (InterLymph)". Cancer Epidemiol Biomarkers Prev. 14(4).
The variant C allele of CYP1A2 was associated with an increased risk of NHL overall among smokers. Increased risk of DLBCL among non-smokers with the GSTP1 variant G allele as well as the CYP1A1 variant G allele was seen. Decreased risk of DLBCL was seen among non-smokers with a variant G CYP1B1 allele. CYP1A1 is involved in estrogens catabolism and the conversion of estrone and estrodiol to water-soluble metabolites, thus affecting estrogenic function and potentially impacting rates of hormone related carcinogenesis. Finding of genetic variation in CYP1A1 and an increased risk of DLBCL in non-smokers is biologically plausible as smoking typically lowers estrogens level, making a clear effect of this mechanism more in non-smokers. CYP1B1 is involved in the activation of benzo[a]pyrene, chemical found in tobacco smoke, and mutations in CYP1B1 significantly decrease the enzyme's ability to metabolize such carcinogens. The GSTP1 variant investigated consists of an A-to-G substitution at base pair 313 at codon 105 resulting in an amino acid difference, from isoleucine to valine.
Kilfoy, B. A., Zheng, T., Lan, Q., Han, X., Qin, Q., Rothman, N., Holford T. and Zhang, Y. (2009). "Genetic polymorphisms in glutathione S-transferases (GSTs) and cytochrome P450s (CYPs), tobacco smoking, and risk of non-Hodgkin lymphoma". Am J Hematol. 84(5), 279-282.
NAT2 genotype was associated with risk of NHL for specific subtypes and the NAT1*10 genotype is an ''at-risk'' allele. Results suggests that the relationship between NHL and smoking status may be modified by common genetic variation in NAT1 but not NAT2.