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

Abstract

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)

Dehalogenation by Cytochrome P‐450cam: Effect of Oxygen Level on the Decomposition of l,2‐Dibromo‐3‐chloropropane

“…Mass spectral data of hexane-extracted reaction samples indicate that l-bromo-3-chloroacetone (BCA) is a major product of DBCP decomposition under oxygen-rich conditions. Figure 2 compares the electron impact mass spectrum to a mass spectrum obtained by Pearson et al (1990). Abundances at mass-to-charge ratios of 170,172, and 174 are rationalized as the parent molecular ion pattern.…”

“…The P-450, monooxygenase system oxidizes the carbon 2 position of DBCP, producing an unstable bromohydrin which spontaneously eliminates H + B r to form the BCA product. Omichinski et al (1988) and Pearson et al (1990) have also measured DBCP decomposition with whole-cell extracts containing liver microsomal P-450 enzyme. They found that, in an oxygen environment, the enzyme can hydroxylate each of the three carbons of 1,2-dibromo-3-chloropropane (DBCP) to yield a number of metabolites, including BCA if carbon 2 is hydroxylated.…”

DNA damage and cell death induced by 1,2-dibromo-3-chloropropane (DBCP) and structural analogs in monolayer culture of rat hepatocytes: 3-aminobenzamide inhibits the toxicity of DBCP

“…A correlation between the bacterial mutagenicity of DBCP and P450-generated 2-bromoacrolein has been established (Omichinski et al, 1988b). Recently, formation of three additional electrophilic metabolites by P450 oxidation of DBCP was reported to contribute to the bacterial mutagenicity (Pearson et al, 1990a). It is possible that some or all of these metabolites may be involved in DBCP-induced DNA-damage, as well as tissue necrosis, in the liver.…”

“…In addition, DBCP induces extensive DNA damage in several organs in vivo (Teramoto et al, 1980;Omichinski et al, 1987;SCderlund et al, 1988;Brunborg et al, 1990). DBCP may be activated by both P450 and glutathione (GSH) dependent pathways to reactive electrophilic species (Omichinski et al, 1987 andPearson et al, 1990a;.…”

Deguanylation of Guanine Based-Nucleosides and Calf Thymus DNA Induced by Halogenated Alkanes at the Physiological Condition

“…Short-chain halogenated alkanes, which we utilized for the study of deguanylation of guanine based-nucleosides, have been widely used industrially as chemical intermediates, extraction solvents, degreasing compounds, copolymer cross-linking agents, or have been reported to be mutagenic and carcinogenic. [8][9][10][11][12][13][14][15][16][17] Among the sixteen different halogenated alkanes, we observed massive deguanylation of nucleosides by 2-bromo-2-methylpropane (2-B-2-MP), 2,3-dibromopropene (2,3-dBPe), 2-bromopropane (2-BP), bromoethane (BE) and 2-iodopropane (2-IP). …”