PMID- 3127943
OWN - NLM
STAT- MEDLINE
DCOM- 19880426
LR  - 20190727
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 92
IP  - 3
DP  - 1988 Mar 15
TI  - The effect of age on the glucuronidation and toxicity of 
      4,4'-thiobis(6-t-butyl-m-cresol).
PG  - 453-66
AB  - Age-related changes in glucuronidation may potentially lead to a decrease in 
      excretion of reactive compounds, resulting in enhanced toxic effects. 
      4,4'-Thiobis(6-t-butyl-m-cresol) (TBBC), a major antioxidant in the rubber 
      industry, was selected as a model compound to evaluate glucuronidation as a 
      function of age because it is directly conjugated to UDP-glucuronic acid (UDPGA) 
      without requiring oxidative metabolism. To assess glucuronidation changes in 
      vivo, male F344 rats, 2.5, 16, and 26 months of age, were administered 5 mg 
      [14C]-TBBC/kg (10 microCi/kg) iv and urine and feces were collected for 3 days. 
      Bile was also collected for 6 hr from animals of the same age groups after iv 
      doses of 5 and 25 mg/kg [14C]TBBC. Total radioactivity was determined in all 
      samples and the profile of metabolites in bile analyzed by HPLC. Along with a 
      decrease in the older animal's ability to excrete TBBC-derived radioactivity in 
      bile, feces, and urine, there was a decrease in the percentage of the dose 
      eliminated in bile as glucuronide. In vitro, the microsomal glucuronyltransferase 
      activity using TBBC as a substrate decreased in the senescent animals. The 
      hepatic concentration of the cofactor UDPGA also decreased from 2.5 to 28 months 
      of age. The apparent Vmax for the enzyme decreased as a function of age while the 
      apparent Km decreased for the substrate (TBBC) but not for the cofactor (UDPGA) 
      in the 26-month-old rats. These data suggest that with the decrease in the 
      activity of the enzyme as well as a decrease in the available UDPGA, the ability 
      of the senescent rats to conjugate and excrete TBBC may be altered. Thus, the in 
      vitro decline in TBBC glucuronidation is compatible with the decreased excretion 
      of TBBC-derived radioactivity observed in vivo in old rats. When toxicity was 
      evaluated in 2.5-, 16-, and 26-month-old rats exposed to 0.25% TBBC in their diet 
      for 14 days, no age-related change in the toxicity of TBBC was observed. However, 
      there appeared to be an increase in leukemia in the treated senescent rats.
FAU - Borghoff, S J
AU  - Borghoff SJ
AD  - National Toxicology Program, National Institute of Environmental Health Sciences, 
      Research Triangle Park, North Carolina 27709.
FAU - Stefanski, S A
AU  - Stefanski SA
FAU - Birnbaum, L S
AU  - Birnbaum LS
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Antioxidants)
RN  - 0 (Cresols)
RN  - 0 (Glucuronates)
RN  - 2616-64-0 (Uridine Diphosphate Glucuronic Acid)
RN  - 96-69-5 (4,4'-thiobis(6-tert-butyl-3-cresol))
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Antioxidants/*metabolism
MH  - Bile/metabolism
MH  - Cresols/*metabolism/toxicity
MH  - Glucuronates/*metabolism
MH  - Glucuronosyltransferase/analysis
MH  - Leukemia, Experimental/chemically induced
MH  - Male
MH  - Rats
MH  - Rats, Inbred F344
MH  - Uridine Diphosphate Glucuronic Acid/analysis
EDAT- 1988/03/15 00:00
MHDA- 1988/03/15 00:01
CRDT- 1988/03/15 00:00
PHST- 1988/03/15 00:00 [pubmed]
PHST- 1988/03/15 00:01 [medline]
PHST- 1988/03/15 00:00 [entrez]
AID - 10.1016/0041-008x(88)90185-8 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 1988 Mar 15;92(3):453-66. doi: 
      10.1016/0041-008x(88)90185-8.