Levels of aflatoxin-albumin biomarkers in rat plasma are modulated by both long-term and transient interventions with oltipraz.
The validation process for biomarkers to be used for monitoring the efficacy of preventive interventions in humans includes assessments of whether levels of the biomarker can be modulated in experimental models. From this perspective, the influence of two intervention protocols with the chemopreventive agent oltipraz on rates of formation and disappearance of aflatoxin-albumin adducts has been evaluated in rats chronically exposed to aflatoxin B1. Male F344 rats were treated daily with 20 micrograms aflatoxin B1, p.o. for 35 days. The first strategy employed a standard, long-term intervention in which basal AIN-76A diet was supplemented with 0.05% oltipraz beginning one week before AFB1 treatment and continuing throughout the period of carcinogen exposure. In this setting, treatment with oltipraz reduced the rate of formation of aflatoxin-albumin adducts such that steady-state levels were lowered by > 50% from control values of 400 pmol aflatoxin adducts/mg albumin. The time-course for reaching respective steady-state levels was unchanged, with or without oltipraz intervention. The second intervention strategy utilized a delayed, transient protocol in which oltipraz was fed for 2 weeks beginning 1 week after AFB1 dosing began and ending 2 weeks before AFB1 dosing was completed. This second strategy, which models clinical interventions in chronically exposed individuals, produced a steady decline in aflatoxin-albumin adduct levels that approached a 50% reduction by the end of the AFB1 exposure period. Development of smooth curve functions allowed for the estimation of the ratio of effects between the non-intervention and intervention groups as well as the simultaneous 90% confidence intervals for the aflatoxin-albumin adduct levels. These analyses indicated that long-term intervention with oltipraz produced a statistically significant reduction in levels of the aflatoxin-albumin biomarker at all times throughout aflatoxin exposure. By contrast, a statistically significant decrease in biomarker levels was not seen in the delayed, transient intervention protocol until the ninth day of the intervention. However, once achieved, significant differences from the control group were maintained for the remainder of the aflatoxin exposure period. These changes in aflatoxin biomarker levels are consistent with the cancer chemopreventive outcomes of these intervention protocols in rats. Collectively, these results support the utility of measuring this biomarker as a means for assessing the efficacy or chemopreventive interventions in individuals at high risk for aflatoxin exposure and development of hepatocellular carcinoma.
Egner
P A
PA
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Gange
S J
SJ
Dolan
P M
PM
Groopman
J D
JD
Muñoz
A
A
Kensler
T W
TW
D016604:Aflatoxin B1 / Q000378:metabolism*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015415:Biomarkers; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012709:Serum Albumin / Q000378:metabolism*; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D015415:Biomarkers; D011719:Pyrazines; D012709:Serum Albumin; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D016604:Aflatoxin B1