Molecular Pathways for Nasopharyngeal … – medic.upm.edu.my

 

 

REVIEW ARTICLE

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

Molecular Pathways for Nasopharyngeal Carcinoma focused on
Acetaldehyde, Nitrosamines and Nicotine Exposures

Rabiatul Basria S.M.N. Mydin1, Simon Imakwu Okekpa1, 2

1 Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200

Bertam, Kepala Batas, Pulau Pinang, Malaysia

2 Department of Medical Laboratory Science, Faculty of Health Sciences, Ebonyi State University, Abakaliki, 840001 Ebonyi

state, Nigeria

ABSTRACT

Recently, one of the head and neck tumours located at the nasopharynx epithelium known as nasopharyngeal carci-
noma (NPC) have been associated with few cancer-promoting compounds that derived from alcohol, salt preserved
foods consumptions and tobacco smoking such as acetaldehyde, nitrosamine, nicotine. These cancer-promoting
compounds present the ability to damage the genome and disrupt cellular metabolic processes. This review will
discuss further on the molecular mechanism of acetaldehyde, nitrosamine, nicotine and NPC risk. Acetaldehyde
can exert influence as carcinogen macromolecular adducts to cellular proteins and DNAs whilst nitrosamines that
commonly found in preserved salted foods/diets can contribute as a powerful carcinogen via endogenous nitrosation
and reactives molecules by CYP2E1. Nicotine present in tobacco could reacts with nitrosamine to form NNN and
NNK known as carcinogenic agent. NNK mediates unstable reactive oxygen species that can induce DNA lesion (α
-hydroxylation of NNN at positions 2’and 5’) and microenvironment alteration for tumorigenesis. In conclusion, this
study suggests acetaldehydes, nitrosamine and nicotine may contribute to NPC tumourigenesis.

Keywords: Acetaldehyde, Nitrosamines, Nicotine, DNA adducts, Nasopharyngeal carcinoma

Corresponding Author:
Rabiatul Basria S.M.N. Mydin, PhD
Email: rabiatulbasria@usm.my
Tel: +604-5622351

INTRODUCTION

Nasopharyngeal cancers (NPC) malignancy is rare
in most part of the world but highly predisposed in
Asian endemic (1). NPC is found in the epithelium
of the nasopharynx and the most common type of
oral cancers in certain populations (2-5). Numerous
studies have debate on the NPC risk association with
alcohol (acetaldehyde), smoking (nicotine) and salt
preserved foods/diets (nitrosamines) consumptions (6-
15). Alcohol (Ethanol) is metabolized into acetaldehyde
(AA) through oxidative processes catalyzed by alcohol
dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1)
and other catalase. AA adheres to proteins and DNAs to
generate DNA carcinogenic adducts causing DNA repair
inhibition, DNA methylation and ROS formation (16).
Assimilation of AA induces nasopharyngeal carcinoma
because of the binding of AA to DNA and cellular
proteins triggering the cellular function impairment
leading to a cascade of immunological reactions (17).
Most cancers delineated on the acetaldehyde exertion
mainly occur at the oral cavity, pharynx and larynx (17).
A part than that, it has been reported that intake salt

preserved foods/diets such as salted fish, salted meat and
preserved vegetables contains nitrosamines and nitrite
that could lead to NPC risk (18). Nitrite is naturally
not carcinogenic but becomes a carcinogen through
endogenous nitrosation where the nitrite reacts with
amides and secondary amines to produce nitrosamides
and nitrosamines which present as oncogenic agent
(19, 20). The potent of nitrosamines for carcinogenicity
correlates with frequent or continuous dietary pattern
(20, 21).

Cigarette smoking present as a very high risk factor
for sino-nasal cancers, nasopharyngeal cancers, and
oral cavity cancers (22). Tobacco smoke contains
toxic compound such as nitrosamines (NNK & NNN),
polycyclic aromatic hydrocarbons (PAHs), aromatic
amines, volatile hydrocarbons, aldehydes, nitro
compounds, phenols and inorganic composites (23, 24).
Furthermore, nitrosamines association with nicotine
is devastating to human. During smoking process,
nicotine is transformed into NNAL, NNN and NNK
which are highly toxic (25). Nitrosamines contained
in tobacco substances are generated through a process
known as nicotine and tobacco alkaloid nitrosation.
Nitrosation of nicotine yields NNK and NNA. NNK
found in tobacco smoke is pro-carcinogenic but
requires CYPs activation in order to yield metabolites
that are DNA reactive prompting pyridyloxobutylation,

Mal J Med Health Sci 15(SP2): 64-70, July 2019

64

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

pyridylhydroxybutylation and methylation of DNA
nucleobases to generate DNA adducts (26–30). Note that
the carcinogenic impact of acetaldehyde, nitrosamines
and nicotine could also present in the certain population
diets or lifestyle.

ACETALDEHYDE (AA): DNA, PROTEIN AND LIPID
ADDUCTS

these

CYP2E1 metabolized acetaldehyde via NADPH-
dependent, an acetaldehyde oxidizing system (31).
Dysregulation of
acetaldehyde oxidative
mechanisms could results in the accumulation of
acetaldehyde which are toxic to human cells as
described by Fig 1. Acetaldehyde is electrophilic and
its electrophilic nature enables it to form adducts
through chemical covalent bonding of products to
DNA, proteins and lipids (32-38). Mutagenic effects
of acetaldehyde is exerted through direct interaction
with DNA, leading to lesion such as mutation and
massive chromosomal damage. Induction of mutation
in the hypoxanthine-phosphor-ribosyl-transferase gene
(HPRT1) by acetaldehyde causes impairment in DNA
synthesis and repair through deletion of nucleotide and
elimination of DNA repair processes. Acetaldehyde
could also induce DNA damage by exerting exchange
of sister chromatids (18, 39, 40). Another DNA adduct
induced by acetaldehyde is N2-propano-2’-deoxy-
guanosine which is genotoxic as well as mutagenic and
has the capacity of generating secondary lesions and
consequent cross links between inter strands thereby
impairing DNA replication to promote cell death (32).
It also triggers replication errors, oncogenic mutations
and onco-suppressor genes mutation thereby promoting
(38). Furthermore, N2-ethyl-deoxy-
carcinogenesis
guanosine (N2-Et-dG) has been previously detected in
acetaldehyde/alcohol mediated cancers of the head and
neck (45-48).

Protein adducts formation by acetaldehyde occurs
through the interaction with epsilon amino group in the
lysines and alpha-amino group of the N-terminal amino-
acids (41). This acetaldehyde adducts causes alteration
in the function and structure of proteins. For instance,
formation of acetaldehyde adducts with methyl-guanine

catalyzed by methyltransferase enzyme results
in
impairment of repair mechanisms of DNA which could
induce carcinogenesis (38). Protein adducts causes
impairment of catalytic reactions and consequent
impairment of the function of NADPH-dependent
CYP2E1 leading to more accumulation of acetaldehyde
as described by Fig. 2.

Figure 2: Schematic described the possible molecular mech-
anisms of Acetaldehyde-Mediated Nasopharyngeal Carci-
noma (NPC). Alcohol is metabolized into acetaldehyde (AA)
which stimulate pathways for carcinogenesis. AA then cause
direct lesions on the DNA with resultant mutations. AA forms
indirect covalent bonds with proteins to impair DNA repair
mechanisms, and increase carcinogenesis potential. AA reacts
with DNA to form DNA adducts. Persistent consumption of
alcohol induces CYP2E1 resulting in reactive oxygen species
(ROS) formation and consequent lipid peroxidation proceeded
by DNA adducts formation. AA-protein adducts rejoin with
DNA adducts to form hybrid adducts.

Acetaldehyde binds to glutathione triggering oxidative
stress which progressed to lipid peroxidation (42).
Lipid peroxidation mediates acetaldehyde induced
carcinogenesis (43, 44). Induction of CYP2E1 in chronic
alcoholic drinkers potentiate reactive oxygen species
(ROS) generation resulting in the perpetuation of
oxidative stress plus consequent cell death (32, 38, 40,
49). The generated ROS radicals (hydroxyethyl radical &
superoxide anion) react with DNA, lipids and proteins
to form adducts. ROS stimulates lipid peroxidation
products such as 4-hydroxynonenal
(4-HNE) and
malondi-aldehyde (MDA) to be formed (Fig. 2) (38, 40).
Aldehydes generated in cells cross-react to generate
hybrid adducts. Combinations of MDA-acetaldehyde
with protein
forms malondialdehyde-
acetaldehyde (MAA) hybrid adducts (Fig. 2). This hybrid
adducts acts synergistically to increase carcinogenic
activities of various adducts (34, 49). Hybrid adducts
perpetuate genotoxicity by stabilizing protein adducts
(50).

adducts

Presence of acetaldehyde reduces
the ability of
the hepatocytes to metabolize carcinogens such as
nitrosamines leading to accumulation of nitrosamines

Figure 1: Potential molecular mechanisms of cancer-promot-
ing compounds such as acetaldehyde, nitrosamine, nicotine.
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
Example:
(NNK), N’-nitrosonornicotine
(NNN). 4-(Methylnitrosami-
no)-1-(3-pyridyl)-1-butanol (NNAL).

65

Mal J Med Health Sci 15(SP2): 64-70, July 2019

tissues

in the peripheral tissue activated by CYP2E1 in the
mucosa. Inducible CYP2E1 expression exposes the
peripheral
to pathogens and carcinogenic
substances due to low specificity of the nitrosamines
to CYP2E1 (51) and generates harmful acetaldehyde
which is highly reactive in tissues which results in
oxidative stress
the
peripheral epithelium to carcinogenic metabolites such
as aflatoxin, aromatic hydrocarbons and nitrosamines
(51). Therefore, acetaldehyde is considered as potential
carcinogen which also commonly associated with upper
aerodigestive cancers.

thereby exposing

influences,

NITROSAMINE FROM SALT-PRESERVED FOODS

Furthermore, few vivo studies have revealed that
salted fish consumption associated with the source
of nitrosamines and plays an etiological role in the
oncogenesis of NPC (52, 53). Diethyl-nitrosamine and
dimethylnitrosamine (DMNA) have previously been
tested in more than 20 species of human and non-
human primates and it was discovered kindred with
tumour induction. For nitrosamine fed rats, the tumour
induction seen started at the nasal cavity. Nitrosamines
is metabolized into reactive carcinogenic molecules by
CYP2E1 and are expressed mainly in the epithelium of
the nasal cavity of animals including humans. Exposure
of humans to already formed N- nitroso compounds
(NOC), nitrosating agents and precursors react in
vivo to generate diazo compounds and carcinogenic
NOC. Some bacteria reduces nitrate to form nitrite,
which is further converted into carcinogenic N-nitroso
compounds (54).

In addition, nitrite and other nitrosating agents can
endogenously be synthesized by bacteria mediated
enzyme reactions, activated neutrophil and macrophages
(54). Neutrophil and macrophages generate nitric
oxide radical through a reaction catalyzed by nitric
oxide synthase. This generated nitric oxide radicals is
cytotoxic and believed to contribute in the generation
of carcinogenic nitrosamines, deamination of DNA base
and oxidative damage (54).

The processes employed in preserving fish and other
diets with salt are very inefficient and causes partial
putrefaction of the diets and fish, thereby, triggering
high levels of nitrosamines accumulation which are
carcinogens in human and other animals (55-59). Salt
preserved fish may possess Epstein-Barr virus (EBV)
reactivating substances, bacterial mutagens and direct
geno-toxins which all contribute to the association with
NPC risk (60-61).

NICOTINE
DEVELOPMENT

AND NITROSAMINES

IN NPC

Tobacco specific nitrosamines, induces formation of
DNA adducts, protein adducts and lipid adducts through

impairment in the signaling pathway of PI3K-Akt, and
Erk-MAP kinase resulting in mutagenesis, altered CYP
450 expression and consequent ROS accumulation thus
exerting oxidative stress and DNA damage as described
by Fig. 1. Tobacco smoke possess carcinogens derived
from nitrosamines (NNAL, NNK & NNN), polycyclic
aromatic hydrocarbons
(PAHs), aromatic amines,
volatile hydrocarbons, aldehydes, nitro compounds,
phenols and inorganic composites (62, 63). Nitrosamines
contained in tobacco substances are generated through
a process known as nicotine and tobacco alkaloid
nitrosation. Nitrosamines constitute a very high risk
factor for sino-nasal cancers, nasopharyngeal cancers,
and oral cavity cancers (22). During smoking process,
nicotine reacts with nitrosamine to form NNN and NNK
which are carcinogenic (25).

NNK mediates ROS induced DNA lesion and alteration
of the microenvironment enabling tumor development.
Elevated levels of ROS constantly activate transcription
factors like NF-κB with consequent tumor progression
(64). NNK found naturally in smoke from tobacco is pro-
carcinogenic and naturally inactive but requires activation
through metabolic processes to enable it exercise its
carcinogenic potentials (65–68). CYPs converts NNK
into metabolites that are DNA-reactive which can cause
methylation, pyridyl-hydroxy-butylation and pyridyl-
oxo-butylation in DNA nucleobases and consequent
formation of DNA adducts (Fig. 3). NNK hydroxylation
by α-Methylene produces methyl-diazonium ion and
methane diazo-hydroxide that bonds with DNA to
yield O4-methylthymine, O6-methylguanine
(O6-
mGua) and 7-N-methylguanine (7-mGua) (69). NNK
α-Hydroxylation could occur at the methylene carbon
or methyl carbon. α-hydroxy-methyl-NNK is produced
when α-Hydroxylation reaction occur at the methyl
carbon which could undergo glucuronidation to yield
pyridyl-oxobutyl-diazohydroxide which subsequently
act on the DNA to produce pyridyl-oxo-butylation
(POB) adducts (70, 71).

NNN undergo three reaction types during its metabolism.
Those reactions are; N-oxidation of pyridine, norcotinine
(i.e
formation and pyrrolidine ring hydroxylation
α-hydroxylation at positions 2’and 5’, β-hydroxylation
at positions 3’ and 4’) (72). α-hydroxylation of NNN at
positions 2’and 5’ causes DNA adducts formation in the
NNN pathway. The NNN α-hydroxylation reactions are
catalyzed mainly by CYPs (73). The 2’-Hydroxy NNN
spontaneously undergo ring unwinding to yield pyridyl-
oxo-butyldiazo-hydroxide with identical structure to
the one formed during NNK methyl hydroxylation. The
5’Hydroxylation yields electrophilic diazo-hydroxide
which reacts with DNA to form adducts (65).

Nicotinic-acetylcholine receptors (nAChRs) comprises
of five subunits with either homo pentamers or hetero
pentamers which are responsible for ligand-gated
ion channels formation in the plasma membranes

Mal J Med Health Sci 15(SP2): 64-70, July 2019

66

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

for

(α7nAChRs)

(74). Nicotine mimic acetylcholine to enable it bind
to α subunit of the nAChRs (75). The affinity of the
nicotine to α4β2 heteromeric nicotinic-acetylcholine
receptors (α4β2nAChRs) is higher than the affinity of
the nicotine to α7 homomeric nicotinic-acetylcholine
(76). Smokers usually have
receptors
increased biological activities of α7nAChR with
impaired α4β2nAChR functions. Regrettably, α7nAChR
is responsible
the regulation of cancer cell
stimulating responses while α4β2nAChR is responsible
for the regulation of cancer inhibitory activities thereby
providing discriminatory support for cancer initiation
and progression (77-81). nAChRs has functional
diversity but functions mainly in cation (Ca2+) channels
and contributes
to regulation of various cellular
activities in cell type specific pattern, reflecting different
cellular cancer origins (82, 83). NNK interfere with the
signaling of β-AdrR, stimulating growth and migration
of the epithelial cells in the airway. Upregulated level
of nAChR with simultaneous inhibition of α4β2nAChR
in smokers alters the balance of the microenvironment
thereby promoting α7nAChR activities, thus enhancing
its activities on tumor cells (Fig.3) (84).

CONCLUSION

This study has deliberate about NPC risk from the
precarious metabolic carcinogens such as acetaldehyde,
nitrosamine and nicotine that could possibly derived
from alcohols, salt preserved foods (diets) and tobacco
smoking. Therefore, the best way to prevent and lower
the risk of NPC is by reducing the exposure to the cancer
promoting compounds by having a healthy diet and
active lifestyle.

ACKNOWLEDGMENTS

The authors would like to thank Universiti Sains Malaysia
(Bridging Research Grant: 304/ CIPPT/ 6316184) for
sponsoring this work.

REFERENCES

1.

Parkin, D.M., Whelan, S.L., Ferlay, J., Teppo, L.
and Thomas, D.B., 2002. Cancer incidence in five
continents. Vol. VIII. IARC Scientific Publication
No. 155. Lyon, France: International Agency for
Research on Cancer

2. Ho JH. Genetic and environmental factors in
nasopharyngeal carcinoma. Recent advances in
human tumor virology and immunology. 1971;
275-95.
Sugano H, Sakamoto G, Sawaki S, Hirayama
T. Histopathological
types of nasopharyngeal
carcinoma in a low-risk area: Japan. IARC scientific
publications. 1978; (20):27-39.

3.

4. Zong YS, Zhang RF, He SY, Qiu H. Histopathologic
types and incidence of malignant nasopharyngeal
tumors in Zhongshan County. Chinese medical
journal. 1983; 96(7):511-6.
Chang ET, Adami HO. The enigmatic
epidemiology of nasopharyngeal carcinoma.
Cancer Epidemiology and Prevention Biomarkers.
2006; 15(10):1765-77.

5.

6. Yong SK, Ha TC, Yeo MC, Gaborieau V, McKay
JD, Wee J. Associations of lifestyle and diet with
the risk of nasopharyngeal carcinoma in Singapore:
a case–control study. Chinese journal of cancer.
2017; 36(1):3
Polesel J, Serraino D, Negri E, Barzan L, Vaccher E,
Montella M, Zucchetto A, Garavello W, Franceschi
S, La Vecchia C, Talamini R. Consumption of fruit,
vegetables, and other food groups and the risk
of nasopharyngeal carcinoma. Cancer Causes &
Control. 2013; 24(6):1157-65.

7.

8. Ren JT, Li MY, Wang XW, Xue WQ, Ren ZF, Jia
WH. Potential factors associated with clinical stage
of nasopharyngeal carcinoma at diagnosis: a case–
control study. Chinese journal of cancer. 2017;
36(1):71.

9. Khlifi R, Olmedo P, Gil F, Feki-Tounsi M, Hammami
B, Rebai A, Hamza-Chaffai A. Risk of laryngeal
and nasopharyngeal cancer associated with

from

toxicity

possible

4-(methylnitrosami-
Figure 3: The
(NNK) and N’-nitrosonornicotine
no)-1-(3-pyridyl)-1-butanone
(NNN) exposures. NNK reacts with α7nAChR while NNN reacts with
αβnAChRs to activate voltage gated-Ca2+ channel promoting Ca2+
influx into the cells and consequent depolarization of the membrane.
This Ca2+ influx activates protein kinase C, serotonin, RAF1, extracel-
lular signal-regulated kinases 1&2 (ERK 1 and ERK2), BCL2, causing
proliferation. The pathway of Phosphatidylinositol 3-kinase (PI3K)-
AKT plus NF-κB are also activated in response to the presence of NNK
with resultant stimulation of proliferation and consequent inhibition of
apoptosis

67

Mal J Med Health Sci 15(SP2): 64-70, July 2019

arsenic and cadmium in the Tunisian population.
Environmental Science and Pollution Research.
2014; 21(3):2032-42

10. Xie SH, Yu IT, Tse LA, Au JS, Lau JS. Tobacco
smoking,
risk of
family history, and
nasopharyngeal carcinoma: a case–referent study
in Hong Kong Chinese. Cancer Causes & Control.
2015; 26(6):913-21.

the

11. Lourembam DS, Singh AR, Sharma TD, Singh TS,
Singh TR, Singh LS. Evaluation of risk factors for
nasopharyngeal carcinoma in a high-risk area of
India, the Northeastern Region. Asian Pac J Cancer
Prev. 2015; 16(12):4927-35.

12. He YQ, Xue WQ, Shen GP, Tang LL, Zeng YX,
Jia WH. Household
inhalants exposure and
nasopharyngeal carcinoma risk: a large-scale case-
control study in Guangdong, China. BMC cancer.
2015; 15(1):1022.

13. Ekpanyaskul C, Sangrajrang S, Ekburanawat W,
Brennan P, Mannetje A, Thetkathuek A, Saejiw
N, Ruangsuwan T, Boffetta P. Semi-quantitative
exposure assessment of occupational exposure
to wood dust and nasopharyngeal cancer risk.
Asian Pacific Journal of Cancer Prevention. 2015;
16(10):4339-45.

14. Ghosh SK, Singh AS, Mondal R, Kapfo W, Khamo
V, Singh YI. Dysfunction of mitochondria due to
environmental carcinogens
in nasopharyngeal
carcinoma in the ethnic group of Northeast Indian
population. Tumor Biology. 2014; 35(7):6715-24.

15. Lakhanpal M, Singh LC, Rahman T et al.
Contribution of susceptibility locus at HLA class I
region and environmental factors to occurrence of
nasopharyngeal cancer in Northeast India. Tumor
Biology. 2015; 36(4):3061-73.

16. Seitz HK, Mueller S. Alcohol and cancer: an
overview with special emphasis on the role of
acetaldehyde and cytochrome P450 2E1.
In
Biological Basis of Alcohol-Induced Cancer
Springer, Cham 2015; 59-70.

17. Pöschl G, Seitz HK. Alcohol and cancer. Alcohol

and alcoholism. 2004; 39(3):155-65.

18. Ward MH, Pan WH, Cheng YJ, et all.PH, Yang
CS, Hildesheim A. Dietary exposure to nitrite and
nitrosamines and risk of nasopharyngeal carcinoma
in Taiwan. International journal of cancer. 2000:
86(5):603-9

19. National Research Council. The health effects of
nitrate, nitrite, and N-nitroso compounds: National
Academy of Sciences. Washington, DC. 1985.
20. Lijinsky W, Taylor HW. Nitrosamines and their
precursors in food. In (HH Hiat, JD Watson and
JA Winsten, eds.), Origin of Human Cancer. 1977;
1579-1590.
International Agency for Research on Cancer.
Tobacco habits other than smoking, betel-quid and
areca-nut chewing, and some related nitrosamines.
In Tobacco habits other than smoking, betel-
quid and areca-nut chewing, and some related

21.

22.

23.

nitrosamines 1985.
Hecht SS. Tobacco carcinogens, their biomarkers
and tobacco-induced cancer. Nature Reviews
Cancer. 2003; 3(10):733.
IARC Working Group on
the Evaluation of
Carcinogenic Risks to Humans, World Health
Organization, International Agency for Research
on Cancer. Tobacco smoke and
involuntary
smoking. Iarc; 2004.

24. Hukkanen J, Jacob P, Benowitz NL. Metabolism and
disposition kinetics of nicotine. Pharmacological
reviews. 2005; 57(1):79-115.

25. Warren GW, Singh AK. Nicotine and lung cancer.

Journal of carcinogenesis. 2013; 12.

26. Sturla SJ, Scott J, Lao Y, Hecht SS, Villalta PW.
Mass spectrometric analysis of relative levels
of pyridyloxobutylation adducts formed in the
reaction of DNA with a chemically activated
carcinogen
form
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Chemical research in toxicology. 2005; 18(6):1048-
55.

tobacco-specific

the

of

27. Kiyohara C, Yoshimasu K, Takayama K, Nakanishi
Y. EPHX1 polymorphisms and the risk of lung
cancer: a HuGE review. Epidemiology. 2006;
17(1):89-99.

28. Kiyohara C, Yoshimasu K, Takayama K, Nakanishi
Y. NQO1, MPO, and the risk of lung cancer:
a HuGE review. Genetics in Medicine. 2005;
7(7):463.

the

lung

tobacco-specific

29. Hecht SS, Carmella SG, Kenney PM, Low SH,
Arakawa K, Mimi CY. Effects of cruciferous
vegetable consumption on urinary metabolites
of
carcinogen
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
in Singapore Chinese. Cancer Epidemiology and
Prevention Biomarkers. 2004; 13(6):997-1004.
. Kunitoh S, Imaoka S, Hiroi T, Yabusaki Y, Monna
T, Funae Y. Acetaldehyde as well as ethanol
is metabolized by human CYP2E1. Journal of
Pharmacology and Experimental Therapeutics.
1997; 280(2):527-32.
Seitz HK, Becker P. Alcohol metabolism and
cancer risk. Alcohol Research & Health. 2007;
30(1):38.

31.

30.

33.

34.

32. Tuma J, Casey CA. Dangerous byproducts of
alcohol breakdown-focus on adducts. Alcohol
Research and Health. 2003; 27:285-90.
Brooks PJ, Theruvathu JA. DNA adducts from
acetaldehyde:
for alcohol-related
implications
carcinogenesis. Alcohol. 2005; 35(3):187-93.
Niemela O. Acetaldehyde adducts in circulation.
InNovartis Foundation Symposium 2007 Apr 30
(Vol. 285, p. 183). Chichester; New York; John
Wiley; 1999.
Setshedi M, Wands JR, de la Monte SM.
Acetaldehyde adducts in alcoholic liver disease.
Oxidative medicine and cellular longevity. 2010;
3(3):178-85.

35.

Mal J Med Health Sci 15(SP2): 64-70, July 2019

68

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

49.

69

Thiele GM, Klassen LW, Tuma DJ. Formation and
immunological properties of aldehyde-derived
protein adducts following alcohol consumption.
InAlcohol 2008 (pp. 235-257). Humana Press.
Barry RE. Role of acetaldehyde in the pathogenesis
of alcoholic liver disease. British journal of
addiction. 1988; 83(12):1381-6.
Marietta C, Thompson LH, Lamerdin
JE,
Brooks PJ. Acetaldehyde stimulates FANCD2
monoubiquitination, H2AX phosphorylation, and
BRCA1 phosphorylation in human cells in vitro:
implications for alcohol-related carcinogenesis.
Mutation Research/Fundamental and Molecular
Mechanisms of Mutagenesis. 2009; 664(1):77-83.
Seitz HK, Stickel F. Molecular mechanisms of
alcohol-mediated carcinogenesis. Nature Reviews
Cancer. 2007; 7(8):599.
Brooks PJ. DNA damage, DNA repair, and alcohol
toxicity—a review. Alcoholism: Clinical and
Experimental Research. 1997; 21(6):1073-82.
Freeman TL, Tuma DJ, Thiele GM, Klassen LW,
Worrall S, Niemelä O, Parkkila S, Emery PW,
Preedy VR. Recent advances in alcohol-induced
adduct
formation. Alcoholism: Clinical and
Experimental Research. 2005; 29(7):1310-6.
Lieberman M, Marks AD. Marks’ basic medical
biochemistry: a clinical approach. Lippincott
Williams & Wilkins; 2009.
Nagata K, Suzuki H, Sakaguchi S. Common
pathogenic mechanism
development
progression of liver injury caused by non-alcoholic
or alcoholic steatohepatitis. The
Journal of
toxicological sciences. 2007; 32(5):453-68.
Albano E. Free radical mechanisms in immune
reactions associated with alcoholic liver disease.
Free Radical Biology and Medicine. 2002;
32(2):110-4.
Matsuda T, Yabushita H, Kanaly RA, Shibutani
S, Yokoyama A. Increased DNA damage in
ALDH2-deficient alcoholics. Chemical research in
toxicology. 2006; 19(10):1374-8.
Nagayoshi H, Matsumoto A, Nishi R, Kawamoto T,
Ichiba M, Matsuda T. Increased formation of gastric
N 2-ethylidene-2’-deoxyguanosine DNA adducts
in aldehyde dehydrogenase-2 knockout mice
treated with ethanol. Mutation Research/Genetic
Toxicology and Environmental Mutagenesis. 2009;
673(1):74-7.
Fang JL, Vaca CE. Detection of DNA adducts of
acetaldehyde in peripheral white blood cells of
alcohol abusers. Carcinogenesis. 1997; 18(4):627-
32.

in

JR, de

la Monte SM.
Acetaldehyde adducts in alcoholic liver disease.
Oxidative medicine and cellular longevity. 2010;
3(3):178-85.
Tuma DJ, Thiele GM, Xu D, Klassen LW, Sorrell
MF. Acetaldehyde and malondialdehyde react
together to generate distinct protein adducts in

50.

51.

the liver during long-term ethanol administration.
Hepatology. 1996; 23(4):872-80.
Niemela O. Aldehyde-protein adducts in the liver
as a result of ethanol-induced oxidative stress.
Front Biosci. 1999; 4:D506-13.
Seitz HK, Stickel F. Molecular mechanisms of
alcohol-mediated carcinogenesis. Nature Reviews
Cancer. 2007; 7(8):599.

52. Yu MC, Nichols PW, Zou XN, Estes J, Henderson
BE. Induction of malignant nasal cavity tumours in
Wistar rats fed Chinese salted fish. British journal
of cancer. 1989; 60(2):198.

54.

57.

56.

55.

53. Huang DP, Ho JH, Saw D, Teoh TB. Carcinoma
of the nasal and paranasal regions in rats fed
Cantonese salted marine fish. IARC scientific
publications. 1978; (20):315-28.
Bartsch H, Ohshima H, Pignatelli B, Calmels
S. Endogenously formed N-nitroso compounds
and nitrosating agents in human cancer etiology.
Pharmacogenetics. 1992; 2(6):272-7.
Chattopadhyay NR, Das P, Chatterjee K, Choudhuri
T. Higher incidence of nasopharyngeal carcinoma
in some regions in the world confers for interplay
between genetic factors and external stimuli. Drug
discoveries & therapeutics. 2017; 11(4):170-80.
Poirier S, Hubert A, Ohshima H, Bourgade MC,
Bartsch H. Occurrence of volatile nitrosamines
in food samples collected in three high-risk areas
for nasopharyngeal carcinoma. IARC scientific
publications. 1987; (84):415-9.
International Agency for Research on Cancer. IARC
monographs on the evaluation of carcinogenic
risks to humans. Dry cleaning, some chlorinated
solvents and other industrial chemicals. 1995;
63:443-65.
Preston-Martin S. N-nitroso compounds as a cause
of human cancer. IARC scientific publications.
1987; (84):477-84.
Zou XN, Lu SH, Liu B. Volatile N‐nitrosamines and
their precursors in chinese salted fish—a possible
etological factor for NPC in China. International
journal of cancer. 1994; 59(2):155-8.
Shao YM, Poirier A, Ohshima H, et al. Epstein–Barr
virus activation in Raji cells by extracts of preserved
food from high risk areas for nasopharyngeal
carcinoma. Carcinogenesis. 1988; 9(8):1455-7.
Poirier S, Bouvier G, Malaveille C, et al. Volatile
nitrosamine levels and genotoxicity of food samples
from high-risk areas for nasopharyngeal carcinoma
before and after nitrosation. International journal
of cancer. 1989; 44(6):1088-94.
Chen CS, Pignatelli B, Malaveille C, et al. Levels of
direct-acting mutagens, total N-nitroso compounds
in nitrosated fermented fish products, consumed
in a high-risk area for gastric cancer in southern
China. Mutation Research/Fundamental and
Molecular Mechanisms of Mutagenesis. 1992;
265(2):211-21.
Hecht SS. Tobacco carcinogens, their biomarkers

62.

60.

61.

63.

59.

58.

Mal J Med Health Sci 15(SP2): 64-70, July 2019

48. Setshedi M, Wands

65.

64.

and tobacco-induced cancer. Nature Reviews
Cancer. 2003: 3(10):733.
IARC Working Group on the Evaluation of
Carcinogenic Risks to Humans, World Health
Organization, International Agency for Research
involuntary
on Cancer. Tobacco smoke and
smoking. Iarc; 2004.
Lee JW, Kim JH. Activation of the leukotriene B4
receptor 2-reactive oxygen species (BLT2-ROS)
cascade following detachment confers anoikis
resistance in prostate cancer cells. Journal of
Biological Chemistry. 2013; 288(42):30054-63
National Research Council. The health effects of
nitrate, nitrite, and N-nitroso compounds: National
Academy of Sciences. Washington, DC. 1985.
67. Lijinsky W, Taylor HW. Nitrosamines and their
precursors in food. In (HH Hiat, JD Watson and
JA Winsten, eds.), Origin of Human Cancer. 1977;
1579-1590.

66.

68. Fabbri M, Garzon R, Cimmino A,. MicroRNA-29
family reverts aberrant methylation in lung cancer
by