Isotope effects on the metabolism and pulmonary toxicity of butylated hydroxytoluene in mice by deuteration of the 4-methyl group
A comparative test in mice for pulmonary toxicity between butylated hydroxytoluene (2,6-di-tert.-butyl-4-methylphenol, BHT) and 2,6-di-tert.-butyl-4-(alpha, alpha, alpha-2H3)methylphenol (BHT-d3) showed a significantly lower toxic potency of the latter. The rate of in vitro BHT metabolism to 2,6-di-tert.-butyl-4-methylene-2,5-cyclohexadienone (BHT-QM) was slowed by deuterating BHT in the 4-methyl group. On the other hand, the rate of in vitro metabolism to 2,6-di-tert.-butyl-4-hydroxy-4-methyl-2,5-cyclohexadienone (BHT-OH) was increased with the deuteration. A similar isotope effect of the deuterium substitution on the in vivo metabolic rates of BHT was observed. These observations support the concept that the lung damage caused by BHT is mediated by BHT-QM. The pulmonary toxicity of 2-tert.-butyl-4-ethylphenol (4-EP) and their deuterated analogs was also compared. 2-tert.-Butyl-4-(1,1-2H2)ethylphenol (4-EP-d2) showed a significantly lower toxic potency than 4-EP, whereas 2-tert.-butyl-4-(2,2,2-2H3)ethylphenol (4-EP-d3) showed a toxic potency comparable to that of 4-EP. This result is consistent with the hypothesis that a quinone methide metabolite is responsible for the onset of lung damage produced by 4-EP as well as BHT.
- Research Organization:
- Laboratory of Environmental Health and Toxicology, Kyoto Prefectural University, Sakyo-ku, Japan
- OSTI ID:
- 5394714
- Journal Information:
- Toxicol. Appl. Pharmacol.; (United States), Vol. 69:2
- Country of Publication:
- United States
- Language:
- English
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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
DEUTERIUM
ISOTOPE EFFECTS
TOLUENE
TOXICITY
DEUTERIUM COMPOUNDS
LIVER
LUNGS
MICE
ANIMALS
AROMATICS
BODY
DIGESTIVE SYSTEM
GLANDS
HYDROCARBONS
HYDROGEN COMPOUNDS
HYDROGEN ISOTOPES
ISOTOPES
LIGHT NUCLEI
MAMMALS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANS
RESPIRATORY SYSTEM
RODENTS
STABLE ISOTOPES
VERTEBRATES
550501* - Metabolism- Tracer Techniques
560305 - Chemicals Metabolism & Toxicology- Vertebrates- (-1987)