1,3-Dibromopropane:Metabolism and application research

Introduction

1,3-Dibromopropane (Figure1) is widely used in industry in chemical syntheses and has been employed to stabilise wool by cross-linking to render it less susceptible to attack by moths. The “lowest lethal dose”, injected intraperitoneally, is stated to be 750 mg/kg in the mouse but as far as the authors are aware, the metabolism of the compound has not been reported although that of the lower homologue,1,2-dibromoethane in the rat has been described.

Metabolism of 1,3-dibromopropane

As with monobromobutane, the administration of 1,3-dibromopropane to the rat results in a decline in the GSH content of the liver. Biliary excretion of sulphur-containing metabolites ensued and enterohepatic cycling occurred since little radioactivity was detected in faeces; the maintained blood levels of radio-activity observed was consistent with the existence of this process. Not more than traces of bromine-containing material was detected in expired air, and it is unlikely that any unchanged compound or bromine-containing metabolites were excreted by this route. The major urinary metabolite was N-acetyl-S-(l-bromo-3-propyl)-cys-teine and is presumably formed from 1-bromo-3-propyl-S-glutathione arising from the reaction between 1,3-dibromopropane and GSH.

1-Bromopentane was a substrate for cytochrome P-450 and recently Jones and Walsh have shown that hydroxylation of 1-bromopropane occurs and suggested that the bromohydrin so formed may give rise to an epoxide. If a similar reaction occurs with 1,3 dibromopropane then the possibility of the formation of a further series of metabolites arises. By the action of epoxide hydratase, the epoxide might be converted to the corresponding diol, oxidation of which to 3-bromo-2-ketopyruvic acid followed by decarboxylation would lead to the formation of bromoacetic acid. It is interesting that the methyl ester of the glycine conjugate of this acid was tentatively identified, from its mass spectrum, in the mixture of methylated metabolites. Other types of metabolites may be formed by deamination of the substituted cysteines arising as intermediates in the mercapturic acid pathway.Thus S-substituted thiolactates and pyruvates may be formed, the latter being further converted to substituted thioacetic acids which may conjugate with glycineas in the formation of methylthioacetylglycine from iodomethane. The many combinations of these possible biotransformations allow for the formation of more than 30 metabolites from 1,3-dibromopropane. The minor metabolites which havebeen tentatively identified probably arise from a series of reactions involving hydroxylation of the 1,3-dibromopropane followed by the formation of an epoxide from the bromohydrin. This epoxide may then be a substrate for epoxide hydrataseor the glutathione-.S-transferases, One of the possible products from the reaction with GSH, 1-bromo-2-hydroxy-3-propyl-S-glutathione, might react to form a second epoxide at some stage in its metabolic pathway. Such a sequence of reactions would account for the formation of the minor metabolites, except bromoacetylglycine, which have been tentatively identified.[1]

Identification and quantitative determination of four different mercapturic acids

1,3-Dibromopropane (1,3-DBP) was administered i.p. in doses ranging from 5.6 to 54 mg to male Wistar rats. Four different mercapturic acids, viz. N-acetyl-S-3-bromopropyl-(MA I), N-acetyl-S-3-chloropropyl-(MA II), N-acetyl-S-2-carboxyethyl-(MA III) and N-acetyl-S-3-hydroxypropyl(-1-)cysteine (MA IV) were synthesized and identified as metabolites in urine by g.l.c.-mass spectrometry. 1,1,3,3-Tetradeutero-1,3-dibromopropane was used to study the mechanism of formation of the mercapturic acids in more detail. It was found that in the formation of MA IV a reactive episulphonium ion could be involved. Gas chromatographic quantification of the mercapturic acids (mercapturic acid assay) was correlated with a spectrophotometric thioether determination of the metabolites (thioether test). At doses up to 30 mg of 1,3-dibromopropane, excretion of mercapturic acids was virtually complete in 24 h urine and amounted to about 19% of the dose (11.3% MA I, 4.9% MA II, 2.6% MA III and 0.2% MA IV). From excretion rate curves a half-time t1/2 was calculated as being about 4.5 h. A plateau in the dose-excretion curve was observed at 1,3-DBP doses higher than 40 mg, probably caused by glutathione depletion.[2]

Hepatotoxic and immunotoxic effects produced by 1,3-dibromopropane and its conjugation

To determine a possible role of glutathione (GSH) conjugation in 1,3-dibromopropane (1,3-DBP)-induced hepatotoxicity and immunotoxicity, female BALB/c mice were treated orally with 1,3-dibromopropane. Based on the liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS) analyses, two forms of S-bromopropyl GSH were observed at m/z 427.9 and 429.9 in the positive ESI spectrum with a retention time of 5.29 and 5.23 min, respectively. Following single treatment of mice with 150, 300 or 600 mg/kg 1,3-dibromopropane for 12 hr, the amount of S-bromopropyl GSH was detected maximally in liver homogenates at 600 mg/kg 1,3-dibromopropane. Hepatic GSH levels were significantly decreased by treatment with 1,3-dibromopropane. In a time course study, production of S-bromopropyl GSH rose maximally 6 hr after treatment and decreased gradually thereafter. The liver weights were significantly increased by treatment with 600 mg/kg 1,3-dibromopropane. When mice were treated orally with 600 mg/kg 1,3-dibromopropane for 12 hr, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased by 365- and 83-fold. In addition, oral 1,3-dibromopropane significantly suppressed the antibody response to a T-dependent antigen at 600 mg/kg 1,3-DBP. 1,3-Dibromopropane elevated hepatic levels of malondialdehyde and suppressed the activities of some hepatic enzymes involved in anti-oxidation. Taken together, the formation of GSH conjugate with 1,3-DBP may deplete cellular GSH and, subsequently, produce hepatotoxicity and immunotoxicity via damage to the cellular anti-oxidative system.[3]

References

[1] James SP, Pue MA, Richards DH. Metabolism of 1,3-dibromopropane. Toxicol Lett. 1981;8(1-2):7-15. doi:10.1016/0378-4274(81)90130-2

[2] Onkenhout W, Van Bergen EJ, Van der Wart JH, Vos GP, Buijs W, Vermeulen NP. Identification and quantitative determination of four different mercapturic acids formed from 1,3-dibromopropane and its 1,1,3,3-tetradeutero analogue by the rat. Xenobiotica. 1986;16(1):21-33. doi:10.3109/00498258609043502

[3] Lee SK, Lee DJ, Jeong H, et al. Hepatotoxic and immunotoxic effects produced by 1,3-dibromopropane and its conjugation with glutathione in female BALB/c mice. J Toxicol Environ Health A. 2007;70(15-16):1381-1390. doi:10.1080/15287390701434489

You may like