RQ2 - Name: Key Due: Review Questions il - Nitrosamines 1....

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Unformatted text preview: Name: Key Due: Review Questions il - Nitrosamines 1. Complete the a-hydroxylation pathways on the right as shown on the left. Nu represents a nucleophile (glutathione, nucleic acid, protein); [ ] denotes an unstable compound. N==O a. Methyiethylnitrosamine I CH3-N—CH2-CH3 OH NmO WNW- \ O=N OH \- I? I I [CHg-NnCHg-CHS] I l [CHa-N-CH-CHg] \ N-OH [CM3*N=N—OH] + oat-mag H CHQO + [N-CHg-CHS] Q 2/ E HO' + N2 + “CHE—CH3] V \HQO, HO- 1 Nu—CHg-CHa HO-CHg-CHS N “ CH3 “‘5 “*3 D. W (W N ' to ' N530 OH o [03 ]<-[@@l<——J——> [W J-» J ‘ [11:0 H N \ g-OH N50 I Q Nz’r\o *3 a"; +110" 4 “03+Ng +[@'+r\§‘°] N | H10 N“ / \Hlo, Hor Mm \\ CH2 Ma" 0 Nut C370 9* ‘3 0 5a ‘ ~ 9? H w 2. Diethylnitrosamine gives rise to tumors of hamster lung but dimethylnitrosamine does not. a. Assuming these agents have equal access to the target cells, give two plausible explanations for this difference in susceptibility. (l) DEN is metabolized in lung but DMN is not. (2) Methylated DNA in lung is repaired efficiently but ethylated DNA is not. b. Would you“, predict that hamster lung is susceptible to tumors caused by administration of ethyimethyinitrosamine? Explain. Yes unless both (1) and (2) above are true. N=O I CHBHNMCHz-CH3 -—> [CH3+] if the ethyl side chain is Oc—hydroxylated. This is likely to be carcinogenic if it is not repaired too rapidly. 3. Give by inspection the stable a—hydroxyiation products expected from the following compounds. (You may assume a nucleophile Nu is present.) N=O CH —ce —ca —cao 3 2 2 a. CH3-CHg-CH2-CH2'N-CH2-CH2—CH2-CH3 CHB—Cflz—CHZ—CHZOH N 2 *0H CH3 CH3 I I b. CFb-C-N -C-CH3 wa I I I H30 N CH3 II 0 0' Hf" 3H2 OCH~CH2~CH2—CH20H H20 CH2 N2 \/ “OH N l N=o d. H2C -CH2 / \ OCH-CHz-CHz—CHOH-COOH HZC CH - CQOH HOCHz—CHZ—CHZ-CO—COOH \ / N2 N -OH I N=O 4. Compound a above (N-nitrosodi-n-butylamine) is carcinogenic in rats while compound b above (N-nitrosodi-t-butylamine) is not. Explain why this finding does or does not support the belief that a-hydroxylation is important for generation of carcinogenic metabolites. Consistent because a can give alkylating species and is active, while 2 does not give alkylating species and is inactive. 5. Compound 0 above (N-nitrosopyrrolidine) is carcinogenic while compound d (N-nitrosoproline) is not. Can these findings be rationalized in terms of metabolism? Explain. N—nitrosoproline is poorly metabolized by oC—hydroxylation, more than 90% being excreted unchanged. 6. What alkylating species is generated in solution from the unstable nitrosourea be‘ow? Why is this nitrosourea unstable? CH3-CH2-N-C-NHg —3n [CH3—CH2+] I II C}:N C) This compound, ethylnitrosourea, is similar in stability to methynitrosourea. Both undergo hydrolysis at neutral and alkaline pH. ...
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This note was uploaded on 03/27/2011 for the course ETX 103A taught by Professor Etx during the Winter '06 term at UC Davis.

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RQ2 - Name: Key Due: Review Questions il - Nitrosamines 1....

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