Chemopreventive effects of dithiocarbamates on aflatoxin B1 metabolism and formation of AFB1 adducts with glutathione.
Several agents with anticarcinogenic potential such as diethyldithiocarbamate (DDTC), lactose-DDTC, proline-dithiocarbamate (PDTC), its dimer proline-thiuramdisulfide (PTDS) and 4-carboxy-piperazine-TDS (4-pip-TDS) were investigated for their influence on the metabolism and the detoxication of aflatoxin B1 (AFB1) in vitro and in vivo. Aflatoxins are a group of mycotoxins produced by aspergillus species and are among the most important risk factors for hepatocellular carcinoma in certain areas of the world. AFB1 metabolism measured by the formation of tris-diol adducts showed that the thiuramdisulfides 4-carboxy-piperazine-TDS and PTDS were better inhibitors in vitro than the corresponding dithiocarbamates. Ex vivo studies in rats showed that dithiocarbamates (DTCs) including sugar linked lactose-DDTC decreased the formation of tris-diol adducts. Among the dithiocarbamates administered, DDTC showed a 40% inhibition whereas the other compounds showed only marginal effects. In vivo experiments on the formation of glutathione-adducts derived from AFB1-endo- and exo-epoxides showed that lactose-DDTC enhanced the formation of AFB1-GSH adducts, whereas PDTC, 4-pip-TDS, PTDS and DDTC displayed inhibitory effects. We conclude that DTCs may be promising agents in the chemoprevention of liver carcinogenesis caused by AFB1.
Gopalaswamy
U V
UV
Radiation Biology and Biochemistry Division, Bhabha Atomic Research Centre, Trombay, Bombay, India.
Frei
E
E
Frank
N
N
Kliem
H C
HC
Wiessler
M
M
Bertram
B
B
Bhattacharya
R K
RK
D016604:Aflatoxin B1 / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D019281:Dimerization; D005978:Glutathione / Q000378:metabolism*; D008658:Inactivation, Metabolic; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline; D016604:Aflatoxin B1; D005978:Glutathione