Metabolic activation of 1,2-dibromo-3-chloropropane to mutagenic metabolites: detection and mechanism of formation of (Z)- and (E)-2-chloro-3-(bromomethyl)oxirane.
1,2-Dibromo-3-chloropropane (DBCP), a haloalkane nematocide and soil fumigant, is metabolically activated to chemically reactive species that are direct-acting mutagens in a Salmonella typhimurium TA 100 test system. Studies in vitro with rat liver microsomes indicated that oxidation at carbon 3 resulted in the formation of an unstable gem-chlorohydrin that rearranged with elimination of hydrogen bromide to form (Z)-2-chloro-3-(bromomethyl)oxirane [(Z)-CBPO] and (E)-2-chloro-3-(bromomethyl)oxirane [(E)-CBPO]. Gas chromatography-mass spectrometry (GC-MS) with positive ion chemical ionization (CI) was employed to identify (Z)-CBPO and (E)-CBPO by comparison of characteristic fragment ions in their CI mass spectra with those observed for authentic standards. Quantitative GC-MS methodology was exploited to quantitate the rate of formation of (Z)-CBPO and (E)-CBPO from DBCP and analogues of DBCP specifically deuterated at carbon 1 and carbon 3. The rate of formation of Z- and E-isomers of CBPO was 31 and 33 pmol/(min.mg of protein), respectively, from DBCP; substitution with deuterium at carbon 1 increased the rate of epoxide formation by 50%, whereas CBPO formation could not be detected from a substrate labeled with deuterium at carbon 3. Both epoxides were directly acting mutagens to S. typhimurium TA 100. (Z)-CBPO caused approximately twice as many his+ revertants/nmol compared to (E)-CBPO. Oxidation at carbon 2 of DBCP resulted in the formation of a bifunctional alkylating agent, 1-bromo-3-chloroacetone, presumably via the intermediacy of an unstable gem-bromohydrin.(ABSTRACT TRUNCATED AT 250 WORDS)
Pearson
P G
PG
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Omichinski
J G
JG
Myers
T G
TG
Søderlund
E J
EJ
Dybing
E
E
Nelson
S D
SD
D000969:Antinematodal Agents / Q000378:metabolism*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004988:Ethers, Cyclic / Q000378:metabolism*; D007306:Insecticides / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D010084:Oxidation-Reduction; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects
D000969:Antinematodal Agents; D004988:Ethers, Cyclic; D007306:Insecticides; D009153:Mutagens; C072543:2-chloro-3-(bromomethyl)oxirane; D003577:Cytochrome P-450 Enzyme System; C007318:1,2-dibromo-3-chloropropane; D011407:Propane