Metabolism of selectively methylated and deuterated analogs of 1,2-dibromo-3-chloropropane: role in organ toxicity and mutagenicity.
In vitro bromide release and in vivo glutathione (GSH) depletion in rat liver, kidney and testis by 1,2-dibromo-3-chloropropane (DBCP) and selectively methylated and deuterated DBCP analogs were studied. With liver microsomes from phenobarbital-pretreated rats the bromide release from the C1-C3-D4- and the perdeuterated DBCP analogs were 54% and 26% of that of DBCP, respectively. Inhibitors of P-450 reduced the bromide release to 10-20% of that without additions. This correlated with the effects of deuterium substitution and additions of P-450 inhibitors on DBCP-induced bacterial mutagenicity as reported elsewhere by this laboratory. To study the importance of GSH-dependent metabolism in DBCP toxicity, bromide release was assayed in cytosolic preparations using methylated analogs of DBCP. With the C1-methyl-derivative, bromide release was markedly reduced compared to that with DBCP in cytosols from liver, kidney and testis. A similar reduction in in vivo nephrotoxicity and testicular damage has recently been reported. The obtained correlation between in vitro GSH-dependent metabolism of methylated DBCP analogs and their in vivo organ damaging potential, points to an involvement of GSH-dependent metabolism in DBCP-induced in vivo toxicity. Both DBCP and the methylated analogs (360 mumol/kg i.p.) depleted the GSH levels in liver after 1 and 3 h and in kidney after 1 h, whereas in the testis no significant depletion of GSH was obtained. As kidney and testis are reported to be the primary target organs for DBCP, there was an apparent lack of correlation between tissue depletion of GSH and organ toxicity.
Låg
M
M
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Søderlund
E J
EJ
Omichinski
J G
JG
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D001965:Bromides / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003903:Deuterium; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship; D013737:Testis / Q000378:metabolism; D013997:Time Factors
D001965:Bromides; D009153:Mutagens; C007318:1,2-dibromo-3-chloropropane; D003903:Deuterium; D005978:Glutathione; D011407:Propane