口腔癌位居台灣男性死亡率的第五位。之前的研究中，我們偵測到粒線體DNA中之4977 bps片段缺失會隨著口腔癌的致癌過程產生量的變化。D-loop區域在粒線體DNA (mtDNA)的複製與轉錄過程中扮演著重要的角色，並過去文獻曾報導在腫瘤組織中該區於有相當高的突變率。本研究中針對雷射顯微切割技術分離之正常口腔上皮、患者之口腔癌前與癌症組織，和16株不同口腔癌臨床分期的癌前與癌症細胞株,以及正常口腔角質細胞(hNOK)之mtDNA的D-loop區域進行突變分析。並利用即時定量PCR(QRT-PCR)方法進行mtDNA copy number的定量。結果顯示細胞株在D-loop區域的突變率明顯比檢體低。在細胞株中，突變發生的主要分佈位置介於 (np) 54~354 (heavy strand) 和 154~454 (light strand)之間；然而，臨床癌組織的突變則介於np134~504 (heavy strand)之間。在15株口腔癌細胞株中，有10株的mtDNA copy number和hNOK細胞比較起來呈現出下降的趨勢，而癌前細胞株(DOK)則是略微上升，其mtDNA copy number介於正常和癌細胞之間。在臨床檢體方面，癌症組織的mtDNA copy number和癌前與正常組織相比呈現出明顯的下降。同時我也發現在臨床檢體上，mtDNA copy number與mtDNA的突變率間是呈一負相關的關係。本研究的結果顯示，在口腔癌致癌過程中，mtDNA之D-loop區域突變的累積主要集中於mtTFA 的結合位置與heavy strand的複製原點。癌前病灶組織與癌症組織相較有較高的突變率與分佈較廣的突變位置。口腔癌細胞株則有較低的突變率。在癌症組織中，mtDNA D-loop區段的突變率與mtDNA copy number間是呈一負相關的關係。在口腔癌細胞株與臨床檢體中，4977bps deletion和mtDNA copy number之間也呈現負相關。癌細胞株之研究模型顯示8-OHdG mtDNA damage與mtDNA copy number間成一相反的關係。mtD-loop區域的突變率則時隨著8-OHdG DNA damage的比例增加而增加。綜而言之，本研究發現粒線體DNA之D-loop區段突變率在臨床檢體與細胞株中較之正常組皆有明顯升高且與其氧化性傷害程度有正相關並可能影響到粒線體基因複製效能，而粒線體基因組之4977bps大片段缺損亦與粒線體基因複製效能降低有關聯。然而，在整個致癌過程中，mtDNA D-loop區域突變對mtDNA複製效能影響的機制，及與癌症發生發展之間的關係仍需進一步的探討。

Oral cancer is the fifth leading cause of cancer death in Taiwanese male population. In a previous study, a quantitative alteration of deleted mtDNA 4977bps deletion was detected in the progression of oral carcinogenesis. The displacement loop (D-loop) of mitochondria genome plays important role in mtDNA replication and transcription. A high mutation rate within the region has been reported in other tumors. In the present study, we analyzed mutations in the D-loop region of mtDNA using laser microdissected paired normal, cancer and precancer cells from patients and sixteen cell lines established from cancers of different clinical stages and precancer as well as primary cultured normal oral keratinocytes (hNOK). Quantitative real-time PCR (QRT-PCR) was performed to analyze mtDNA copy number reference to the nuclear DNA. The results indicate a significant lower mutation frequency of the D-loop region in the cell lines compared to the specimens. The hot regions for mutations was distributed between the nucleotide position (np) 54~354 (heavy strand) and 154~454 (light strand) in the cell lines, while microdissected cancer tissues harbored mutations between np134~504 (heavy strand). Ten of fifteen oral cancer cell lines had decreased mtDNA copy number compared with primary cultured hNOK, while the precancer line (DOK) exhibited slightly increased mtDNA copy number between normal and the cancer cell lines. In the clinical samples, significant decreased mtDNA copy number was also observed in cancers compared to normal and precancer tissues. A significant inverse association was found between mtDNA copy number and the D-loop mutation rate in the clinical samples (p<0.01). In conclusion, D-loop mutations were accumulated among mtTFA binding sites and the heavy strand replication origin during oral carcinogenesis. Precancer lesions had a higher mutation rate and broader range of mutation distribution than the cancer tissues did. Oral cancer cell lines presented significantly lower mutation rate compared with those of the clinical specimens. The D-loop mutation rate is inversely associated with mtDNA copy number in cancer tissues. In oral cancer cell lines and clinical specimens, there was a reverse relationship between the 4977bp deletion and copy number of mtDNA. The level of 8-OHdG DNA damage was inversely associated with mtDNA copy number in the cancer cell lines. The mutation frequency of mtDNA D-loop region was also associated with the level of 8-OHdG content in mtDNA. In summary, this study revealed an association between mtDNA D-loop region mutations and oral carcinogenesis progression. The mutation frequency was associated with the mtDNA 8-OHdG oxidative damage and may decrease the mtDNA replication efficiency. The large scale mtDNA deletion was also associated with the decrease in the mtDNA copy number. However, the mechanism for D-loop mutations in oral carcinogenesis progression and their functional effects on the mtDNA replication and cancer development remained to be elucidated.

周文彬. 2003. Studies of mitochondrial DNA 4977 bp deletion in microdissected oral cancer and precancer lesions by real-time quantitative PCR. 國立成功大學分子醫學所碩士論文：23-25.
韓良俊. 2000. 檳榔的健康危害. 健康世界叢書, 144.
Abdi S and Ali A. 1999. Role of ROS modified human DNA in the pathogenesis and etiology of cancer. Cancer Lett 142(1): 1-9.
Ames BN and Gold LS. 1990. Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci U.S.A. 87:7772-7776.
Attardi G and Schatz G. 1988. Biogenesis of mitochondria. Annu Rev Cell Biol 4:289-333.
Azuma Y, Ozasa N, Ueda Y, and Takagi N. 1986. Pharmacological studies on the anti-inflammatory action of phenolic compounds. J Dent Res 65(1):53-56.
Aquadro CF and Greenberg BD. 1983. Human mitochondrial DNA variation and evolution: analysis of nucleotide sequences from seven individuals. Genetics 103(2):287-312.
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, and Young IG. 1981. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465.
Bianchi NO, Bianchi MS and Richard SM. 2001. Mitochondrial genome instability in human cancers. Mutat Res 488(1):9-23.
Bonner RF, Emmert-Buck M, Cole K, Pohida T, Chuaqui R, Goldstein S and Liotta LA. 1997. Laser capture microdissection: molecular analysis of tissue. Science 278:1481-1483.
Burgart LJ, Zheng J, Shu Q, Strickler JG, and Shibata D. 1995. Somatic mitochondrial mutation in gastric cancer. Am J Pathol 147:1105-1111.
Boiteux S, O’Connor TR and Laval J. 1987. Formamidopyrimidine-DNA glycosylase of Escherichia coli: cloning and sequencing of fpg structural gene and overproduction of the protein. EMBO J 5(10):3177-3183.
Bogenhagen DF and Clayton DA. 1977. Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell 11:719-727.
Boveris A, Oshino N and Chance B. 1972. The cellular production of hydrogen peroxide. Biochem J 128:617-630.
Coskun PE, Beal MF and Wallace DC. 2004. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U.S.A. 101(29): 10726-10731.
Carelli V, Giordano C and d’Amati G. 2003. Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction. Trends Genet 19:257-262.
Copeland WC, Wachsman JT, Johnson FM, and Penta JS. 2002. Mitochondrial DNA alterations in cancer. Cancer Invest 20(4): 557-569.
Cummins J. 1998. Mitochondrial DNA in mammalian reproduction. Rev Reprod 3:172-182.
Cheng KC, Cahill DS, Kasai H, Nishimura S, and Loeb LA. 1992. 8-Hydroxyguanine, an abundant from of oxidative DNA damage, causes G→T and A→C substitutions. J Biol Chem 267(1):166-172.
Clayton DA. 1991. Nuclear gadgets in mitochondrial DNA replication and transcription. Trends Biochem Sci 16:107-111.
Cantatore P, Polosa PL, Fracasso F, Flagella Z, and Gadaleta MN. 1986. Quantitation of mitochondrial RNA species during rat liver development, the concentration of cytochrome oxidase subunit Ⅰ (CoⅠ) mRNA increase at birth. Cell Differ 19:125-132.
Cerutti PA. 1985. Prooxidant states and tumor promotion. Science 227(4685): 375-381.
Cann RL, Brown WM and Wilson AC. 1984. Polymorphic sites and the mechanism of evolution in human mitochondrial DNA. Genetics 106(3):479-499.
Chance B, Sies H and Boveris A. 1979. Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527-605
Daga A, Micol V, Hess D, Aebersold R, and Attardi G. 1993. Molecular characterization of the transcription termination factor from human mitochondria. J Biol Chem 268:8123-8130.
Darroudi F and Natarajan AT. 1993. Metabolic activation if chemicals to mutagenic carcinogen by human hepatoma microsomal extracts in Chinese hamster ovary cells. Mutagenesis 8(1): 11-15.
Fernández-Silva P, Enriquez JA and Montoya J. 2003. Replication and transcription of mammalian mitochondrial DNA. Exp Physiol 88:41-56.
Falkenberg M, Gaspari M, Rantanen A, Trifunovic A, Larsson NG, and Gustafsson CM. 2002. Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nat Genet 31:289-294.
Fiss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J, and Sidransky D. 2000. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287:2017-1019.
Fernández-Silva P, Martinez-Azorin F, Micol V, and Attardi G. 1997. The human mitochondrial transcription termination factor (mTERF) is a multizipper protein but binds to DNA as a monomer, with evidence pointing to intramolecular leucine zipper interactions. EMBO J 16:1066-1079.
Fisher RP and Clayton DA. 1988. Purification and characterization of human mitochondrial transcription factor 1. Mol Cell Biol 8:3496-3509.
Fisher RP Topper JN and Clayton DA. 1987. Promoter selection in human mitochondria involves binding of a transcription factor to orientation-independent upstream regulatory elements. Cell 50:247-258.
Fisher RP and Clayton DA. 1985. A transcription factor required for promoter recognition by human mitochondrial RNA polymerase. J Biol Chem 260:11330-11338.
Garesse R and Vallejo CG. 2001. Animal mitochondrial biogenesis and function: a regulatory cross-talk between two genomes. Gene 263:1-16.
Gadaleta MN, Petruzella V, Renis M, Fracasso F, and Cantatore P. 1990b. Reduced transcription of mitochondrial DNA in the senescent rat. Tissue dependence and effect of L-carnitine. Eur J Biochem 187:501-506.
Goto Y, Nonaka I and Horai S. 1990. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of the mitochondrial encephalomyopathies. Nature 348(6302):651-653.
Hood DA. 2001. Invited Review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 90:1137-1157.
Habano W, Sugai T, Nakamura SI, Uesugi N, Yoshida T, and Sasou S. 2000. Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma. Gastroenterology 118:835-841.
Hoffbuhr KC, Davidson E, Filiano BA, Davidson M, Kennaway NG, and King MP. 2000. A pathogenic 15-base pair deletion in mitochondrial DNA-encoded cytochrome c oxidase subunit Ⅲ results in the absence of functional cytochrome c oxidase. J Biol Chem 275:13994-14003.
Hixson JE, Wong TW and Clayton DA. 1986. Both the conserved stem-loop and divergent 5’-flanking sequences are required for initiation at the human mitochondrial origin of light-strand DNA replication. J Biol Chem 261:2384-2390.
Harman D. 1981. The aging process. Proc Natl Acad Sci U.S.A. 78(11): 7124-7128.
Harman D. 1956. Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298-300.
Jeng JH, Wang YJ, Chang WH, Wu HL, Li CH, Uang BJ, Kang JJ, Lee JJ, Hahn LJ, Lin BR, and Chang MC. 2004. Reactive oxygen species are crucial for hydroxychavicol toxicity toward KB epithelial cells. Cell Mol Life Sci 61:83-96.
Jeng JH, Chang MC and Hahn LJ. 2001. Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol 37: 477-492.
Jeng JH, Ho YS, Chan CP, Wang YJ, Hahn LJ, Lei D, Hsu CC, and Chang MC. 2000. Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes. Carcinogenesis 21:1365-1370.
Jin YT, Tsai ST, Wong TY, Chen FF, and Chen RM. 1996. Studies on promoting activity of Taiwan betel quid ingredients in hamster buccal pouch carcinogenesis. Eur J Cancer B Oral Oncol 32B(5)：343-346.
James GR and Michael AB. 1981. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from human squamous cell carcinomas. Cancer Res 41: 1657-1663.
Kirches E, Krause G, Warich-Kirches M, Weis S, Schneider T, Meyer-Puttlitz B, Mawrin C, and Dietzmann K. 2001. High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples. Int J Cancer 93(4):534-538.
Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, Keranen S, Peltonen L, and Suomalainen A. 2000. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:782-785.
Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, Seeberg E, Lindahl T, and Barnes DE. 1999. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci U.S.A. 96(23): 13300-13305.
Kagawa Y, Hamamoto T, Endo H, Ichida M, Shibui H, and Hayakawa M. 1997. Genes of human ATP synthase: their roles in physiology and aging. Biosci Rep 17(2):115-146.
Kehrer JP. 1993. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 23:21-48.
Kim MS, Li SL, and Park NH. 1993. State of p53, Rb and DCC tumor suppressor genes in human oral cancer cell lines. Anticancer Res 13：1405-1413.
Lin PH, Lee SH, Su CP, and Wei YH. 2003. Oxidative damage to mitochondrial DNA in atrial muscle of patients with atrial fibrillation. Free Radic Biol Med 35(10): 1310-1318.
Liu Y, Fiskum G and Schubert D. 2002. Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80: 780-787.
Lee HC, Yin PH, Yu TN, Chang YD, Hsu WC, Kao SY, Chi CW, Liu TY, and Wei YH. 2001. Accumulation of mitochondrial DNA deletions in human oral tissues-effects of betel quid chewing and oral cancer. Mutat Res 493:67-74.
Lee HC, Yin PH, Lu CY, Chi CW, and Wei YH. 2000. Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J 348(Pt2): 425-432.
Lecrenier N and Foury F. 2000. New features of mitochondrial DNA replication system in yeast and man. Gene 246:37-48.
Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, Barsh GS, and Clayton DA. 1998. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet 18(3):231-236.
Lee DY and Clayton D. 1996. Properties of a primer RNA-DNA hybrid at the mouse mitochondrial DNA leading-strand origin of replication. J Biol Chem 271:24262-24269.
Lee HC, Pang CY, Hsu HS, and Wei YH. 1994. Differential accumulations of 4977bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim Biophys Acta 1226(1):37-43.
Lewis JG and Adams DO. 1987. Inflammation, oxidative DNA damage, and carcinogenesis. Environ Health Perspect 76:19-27.
Loschen G, Flohe L and Chance B. 1971. Respiratory chain linked H(2)O(2) production in pigeon heart mitochondria. FEBS Lett 18:261-264.
McCulloch V, Seidel-Rogol BL and Shadel GS. 2002. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds s-adenosylmethionine. Mol cell Biol 22:1116-1125.
MITOMAP. 2001. The report of the committee on the human mitochondrial genome. Center for Molecular Medicine, Emory University, Atlanta, GA.（Available from http://www.mitomap.org）.
Madsen CS, Ghivizzani SC and Hauswirth WW. 1993. Protein binding to a single termination-associated sequence in the mitochondrial DNA D-loop region. Mol cell Biol 13:2162-2171.
Malins DC and Haimanot R. 1991. Major alterations in the nucleotide structure of DNA in cancer of the female breast. Cancer Res 51(19):5430-5432.
Mutvei A, Kuzela S and Nelson BD. 1989. Control of mitochondrial transcription by thyroid hormone. Eur J Biochem 180:235-240
Montoya J, Gaines GL and Attardi G. 1983. The pattern of transcription of the human mitochondrial rRNA genes reveals two overlapping transcription units. Cell 34:151-159.
Montoya J, Christianson T, Levens D, Rabinowitz M, and Attardi G. 1982. Identification of initiation sites for heavy strand and light strand transcription in human mitochondrial DNA. Proc Natl Acad Sci U.S.A. 79:7195-7199.
McGinty F, Delides G and Harrison D. 1973. The significance of enzyme histochemical patterns in carcinomas of the large intestine in man. Gut 14:502-505.
Nomoto S, Yamashita K, Koshikawa K, Nakao A, and Sidransky D. 2002. Mitochondrial D-loop mutations as clonal marker in multicentric hepatocellular carcinoma and plasma. Clin Cancer Res 8(2):481-487.
Nishino I, Spinazzola A and Hirano M. 1999. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689-692.
Nair UJ, Friesen M, Richard I, MacLennan R, Thomas S, and Bartsch H. 1990. Effect of lime composition on the formation of reactive oxygen species from areca nut extract in vitro. Carcinogenesis 11(12):2145-2148.
Nair UJ, Floyd RA, Nair J, Bussachini V, Friesen M, and Bartsch H. 1987. Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients. Chem Biol Interact 63(2):157-169.
Pesce V, Cormio A, Marangi LC, Guglielmi FW, Lezza AM, Francavilla A, Cantatore P, and Gadaleta MN. 2002. Depletion of mitochondrial DNA in the skeletal muscle of two cirrhotic patients with severe asthenia. Gene 286(1):143-148.
Penta JS, Johnson FM, Wachsman JT, and Copeland WC. 2001. Mitochondrial DNA in human malignancy. Mutat Res 488: 119-133.
Prieto-Martín A, Montoya J and Martínez-Azorín F. 2001. A study on the human mitochondrial RNA polymerase activity points to existence of transcription factor B-like protein. FEBS Lett 503:51-55.
Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, and Vogelstein B. 1998. Somatic mutations of the mitochondrial genome in human colorectal tumors. Nat Genet 20(3):291-293.
Rao AR and Das P. 1989. Evaluation of the carcinogenicity of different preparations of areca nut in mice. Int J Cancer 43(4):728-732.
Ranadive KJ, Ranadive SN, Shivapurkar NM, and Gothoskar SV. 1979. Betel quid chewing and oral cancer: experimental studies on hamsters. Int J Cancer 24(6):835-843.
Shieh DB, Chou WP, Wei YH, Wong TY, and Jin YT. 2004. Mitochondrial DNA 4977-bp deletion in paired oral cancer and precancerous lesions revealed by laser microdissection and real-time quantitative PCR. Ann N Y Acad Sci 1011:154-167.
Stevnsner T, Thorslund T, de Souza-Pinto NC, and Bohr VA. 2002. Mitochondrial repair of 8-oxoguanine and changes with aging. Exp Gerontol 37:1189-1196.
Shieh DB, Godleski J, and Kwiatkowski DJ. 1999. Cell motility as a prognostic factor in stageⅠnonsmall cell lung carcinoma: the role of gelsolin expression. Cancer 85(1):47-57.
Suarez-Quian CA, Goldstein SR, Pohida T, Smith PD, Peterson JI, Wallner E, Ghany M and Bonner RF. 1999. Laser capture microdissection of single cells from complex tissues. Biotechniques 26:328-335.
Shadel GS and Clayton DA. 1997. Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem 66:409-435.
Sharan RN and Wary KK. 1992. Study of unscheduled DNA synthesis following exposure of human cells to arecoline and extracts of betel nut in vitro. Mutat Res 278(4):271-276.
Sundqvist K and Graftstrom RC. 1992. Effects of areca nut on growth, differentiation and formation of DNA damage in cultured human buccal epithelial cells. Int J Cancer 52(2):305-310.
Stich HF and Anders F. 1989. The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers. Mutat Res 214(1): 47-61.
Shacter E, Beecham EJ, Covey JM, Kohn KW, and Potter M. 1988. Activated neutrophils induce prolonged DNA damage in neighboring cells. Carcinogenesis 9:2297-2304.
Shmookler RRJ and Goldstein S. 1983. Mitochondrial DNA in mortal and immortal human cells. J Biol Chem 258(15): 9078-9085.
Stich HF, Stich W and Lam PP. 1981. Potentiation of genotoxicity by concurrent application of compounds found in betel quid: arecoline, eugenol, quercetin, chlorogenic acid and Mn2+. Mutat Res. 90(4): 355-63.
Sirsat SM and Kandarkar SV. 1968. Histological changes in the oral mucosa of the wistar rat treated with commercial lime (calcium hydroxide)--an optical and submicroscopic study. Br J Cancer 22(2): 303-15.
Tsuruya K, Furuichi M, Tominaga Y, Shinozaki M, Tokumoto M, Yoshimitsu T, Fukuda K, Kanai H, Hirakata H, Iida M, and Nakabeppu Y. 2003. Accumulation of 8-oxoguanine in the cellular DNA and the alteration of the OGG1 expression during ischemia-reperfusion injury in the rat kidney. DNA repair 2(2):211-229.
Takamatsu C, Umeda S, Ohsato T, Ohno T, Abe Y, Fukuoh A, Shinagawa H, Hamasaki N, and Kang DC. 2002. Regulation of mitochondrial D-loops by transcription factor A and single-stranded DNA-binding protein. EMBO Rep 3:451-456.
Tan DJ, Bai RK and Wong LJC. 2002. Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Cancer Res 62:972-976.
Tang YY, Schon EA, Wilichowski E, Vazquezmemije ME, Davidson E, and King MP. 2000. Rearrangements of human mitochondrial DNA (mtDNA), new insights into the regulation of mtDNA copy number and gene expression. Mol Biol Cell 11:1471-1485.
Tiranti V, Savoia A, Forti F, Dapolito MF, Centra M, Racchi M, and Zeviani M. 1997. Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the expressed sequence tags database. Hum Mol Genet 6:615-625.
Tsujimoto Y, Hashizume H and Yamazaki M. 1993. Superoxide radical scavenging activity of phenolic compounds. Int J Biochem 25(4): 491-494.
Thomas SJ and MacLennan R. 1992. Slaked lime and betel nut cancer in Papua New Guinea. Lancet 340: 577-578.
Wei YH and Lee HC. 2002. Minireview: Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med 227: 671-682.
Wei YH. 1998. Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med 217(1): 53-63.
Wang CK and Lee WH. 1996. Separation, characterization and biological activities of phenolics in areca fruit. J Agric Food Chem 44: 2014-1019.
Wallace DC. 1992. Diseases of the mitochondrial DNA. Annu Rev Biochem 61: 1175-1212.
Wong DY, Chang KW, Chen CF, and Chang RC. 1990. Characterization of two new cell lines derived from oral cavity human squamous cell carcinomas—OC1 and OC2. J Oral Maxillofac Surg 48(4):385-390.
Williams RS. 1986. Mitochondrial gene expression in mammalian striated muscle. Evidence that variation in gene dosage is the major regulatory event. J Biol Chem 261:12390-12394.
Woolverton C, Fotos PG, Mokas MJ, and Mermigas ME. 1986. Evaluation of eugenol for mutagenicity by the mouse micronucleus test. J Oral Pathol 15(8): 450-453.
Wong TW and Clayton DA. 1985. In vitro replication of human mitochondrial DNA, accurate initiation at the origin of light-strand synthesis. Cell 42:952-958.
Walberg MW and Clayton DA. 1983. In vitro transcription of human mitochondrial DNA, identification of specific light strand transcripts from the displacement loop region. J Biol Chem 258:1268-1275.
Xu BJ and Clayton DA. 1996. RNA-DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at replication start sites. An implication for RNA-DNA hybrids serving as primers. EMBO J 15:3135-3143.
Yang CY and Meng CL. 1994. Regulation of PG synthase by EGF and PDGF in human oral, breast, stomach, and fibrosarcoma cancer cell lines. J Dent Res 73:1407-1415.
Yen TC, King KL, Lee HC, Yeh SH, and Wei YH. 1994. Age-dependent increase of mitochondrial DNA deletions together with lipid peroxides and superoxide dismutase in human liver mitochondria. Free Radic Biol Med 16(2):207-214.