Document 096v3eaR8mdyd1qDgBg44VLJ

icriniii:il cntl tit' ilic cI;iss I I /j-clr:iiii ( l i p . I k. 'l'ltcw cxpsriiiicrits \Iio\rs tli;il iI is posrildc l o produce :I c l w d - riot1 hy cells o f cl;iss II proicins hound entirely. or n i o d y . l o ;I singlc peptide will hc. inv;ilu;ihlc in studies of' posilivc sclcclion Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens Paolo Vlnels', Helmut Bartscht, Neil Caporaso:, Anita M. Harringtod, Fred F. Kadlubar , Maria Teresa LandF, Christian Malaveille it, Peter 0. Shields$, Paul Skipper**, aGlenn Talaskaf' Steven R. Tannonbaum** Unil of Cancer Eoidemiology. Dipartimcnto di Scicnzc Diocncdiclic r Oncologia Umana. Univcrsilv and Mdin Iiosoital. 10126 Torino. llnlv TAI?LE 1. LCVCIS Of AOPmcmoglobin adducts hy niCOlint+COtininC in 34.h urine and acetylator QhenOtypein 97 volunteers 4DP.haCrnoplobin adduct Conccntralion (pg per g haemoglobin) Nicolinc colininet Whole group Median Mean 4cctylalor PhWotvDc Rdpid' Slowu' (mcdianl i)cr Cent mCreaSC In slow O r r i 441 . 1 5 (n 25) 1 5 - 2 4 (11 9) 1 5 19, 225 65 128 125 285 795 1237 1353 13 52 92 128 27 99 132 119 107 90 43 -7 Nunibcr of subjccls with ABP adducts above/below median Aceiylator phenotype CSIS. Nation.11 Cancer Institute. Rcscarch. Jefferson. mcthyluracil: 1-melhylxanlhine ratio <O.G. The odds ralios (OR) represent the probabilily of havinga high concentration of adducts (greater avoro. ~~~~d~l M~ilan~o, ~20~122j Mllc,n(,, ~ h a nthe median value) for slow v e m s rapid acetylators. 959'0CI. 95% confidence inlervat. For the analysis of ABP-haemoglobin adducts, iM- Inlcrnational Agency for Research on Cancer, 69372 L ~F~~~~~~ ~ ,latcd haemoglobin was purified by dialysis and then hydrolysed with DePartmcnl of Chcmlstry. Mas%achUsCItSlnstltUlC of T ~ ~ ~ bas, e to~ rele~ase t~he p~arent~amin~e. Af,ter extraction into hexane. the Cambridge. MassachUscIls02 139.4307. USA ainiiic was derivalired to form pentafluoropropionamtdc.Quantification +* Dcpanmcnt of Environmental Healtlr. Univcrsity of Cincinnzrti. Cincinnati. Ohto 558.5397. USA was by comparison of peak areas produced by Ihe analyte and an intcrnnl standard (4'-iluoroJ-aminobiphenyl) upon capillary gas chro- mnfojiraghv. using ncgative-ion chemical.ioniralion mass specttomelry for ucicclion. For dctcrminaIion of the acetylator SlalUS. urine SamplCS w(!ro coil~.ctcd5 h ancr consumptionof onc siitndardizcd CUD of coffee. Caflcinc and 11s melaboliles were extracted as described". The extracts wcre anal\scc by HPLC using a program that separated caffeine and 411tis known mclabolites. Hacmoglobinadducts were analysed at MIT. CJmbrldjie: the rnelabolic phcnolype for the NAT polymorphism was dctrrmined a1 NCTR. Jcffcrson: urinary colinine and nicotine were mcasurtld dl IARC. Lyon. P value for trend -:0.0001.+ units. limo1 nrr nirriol m:.iIintw: I ) rcgrcscnls nirnibcr of subjects. B 154 .NATURE ' VOL 369 12 MAY 1994 . a LETTERS TO NATURE TAQLE 2 Correspondence between NAT2 genotype and acetylator p!ienotype Genotype (number of mutations) 0 1 22 Acetylator DhenOlypC Correlation cocflicicnls n Rapid Slow OR 195"~CI) AFMU/ 1 X versus nicotinc-cotininc a6 2 1.0 - 13 5 R 4 a (0.7-33) 20 1 .19 57 0 (7.0-460) 0.03 ( P 09) 0 3 7 (P 021 0.10IP 0 7) ABP adducts I1 Mean Median Se 08 1 13 2 ' 20 43 2 68 7 69.7 22 56 65 18 5 17 7 12 1 OR.Odds ratio. 9 5 ' a oCl.95) I confitlcncc interval. corrclalion corfftcienls AFMU/l - X ratio versus nicotine-cotlnme (Pvalues). by genotype: and mean 4-nminobiphenyl-~ac~.gfi'obin adducts. by genotype (s e , standard error). The genotype for the MAT2 $!eve was deterrnined using PCR and RFLP on DNA extracted froin ! 'v coal Four mutations have been analysed (M1. M2. M3. M4)* Tne gcnolypp was determined at !he NCI. Bethesda. n Represents number of sub,, JS. TA&E 3 --. .,,., I. -3. Pfes&cc/absence of DNA 3dducls 2 and U in etfol*atrd bladder cells. hr .icelylalor phc',oivDe In 39 Suhiccls Acctvlator nhenulvpc R.1Dld slow 12 17 3 :.G(0.3-7 81 4 i 1 3 tO C-*.GI n 16 LETTERS TO NATURE ?he stress-activated protein kinase subfamily of c-Jun kinases John M. Kyriakis, Papia Banerjee*, Eieni Nlkolakakl*, Tlanang Dalt, Elizabeth A. Rublet, Mir F. Ahmad', Joseph Avruch & lames R. Woodgett'"