Synthesis and Pulmonary Toxicity of Several 3-Furyl Ketones: Evidence for the Position of Metabolism by Cytochromes P-450

Pulmonary toxicity of naturally occurring 3-furyl ketones is of increasing concern to animal science. Bioactivation of these heterocycles by pulmonary cytochromes P-450 is necessary for their toxicity, but the mechanism of this bioactivation is not clearly understood. Using a series of 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (2), it has been shown that the toxicity of these compounds in mice is dependent upon their log P and ('13)C-NMR shift characteristics. Studies were needed to further elucidate the role of the side chain of 3-furyl ketones on toxicity and the position of attack on 3-furyl ketones by cytochromes P-450. 3-Furylphenyl ketone (3), 3-furylphenethyl ketone (4), and 1-(3-furyl)-4,4-dimethylpentan-1-one (5) were synthesized to examine the first problem. The 48 h LD50 (ip) in Notre Dame Swiss mice for these analogues was greater than that of perilla ketone (2, 30 (+OR-) 5; 3, 173 (+OR-) 4; 4, 150 (+OR-) 11; 5, 81 (+OR-) 6 (mu)mol/kg). The reduced toxicity of 3, 4, and 5 cannot be explained on the basis of log P or ('13)C-NMR characteristics. Instead, it is probably due to steric hindrance of bioactivation by the bulky side chain substituents and to protective metabolism of the phenyl ring rather than the furan ring of 3 and 4. Preliminary studies indicated that 1-(2,5-dimethyl-3-furyl)-4-methylpentan-1-one (8) was non-toxic to mice. This finding was confirmed by the synthesis and toxicological testing of 8 (48 h LD50 = 2,238 (+OR-) 1,242 (mu)mol/kg). Therefore, bioactivation must occur at either the #2 or #5 carbon position of the furan ring. To determine which of these positions is involved in bioactivation, 1-(2-methyl-3-furyl)-4-methylpentan-1-one (9) and 1-(5-methyl-3-furyl)-4-methylpentan-1-one (10) were synthesized. The 2-methyl congener has a 48 h mouse LD50 (190 (+OR-) 19 (mu)mol/kg) near that predicted on the basis of chemical parameters. But, the 5-methyl congener was considerably less lethal (8,807 (+OR-) 3,710 (mu)mol/kg). Bioactivation of 3-furyl ketones must then occur at the #5 carbon position. A single sublethal administration (ip) of 10 protected against the toxicity of 2 administered (ip) 1 hr after pretreatment. This protection persisted up to 2 days after pretreatment. No significant protective effect was noted by pretreating with 8 or 9. Additive toxicity was observed with pretreatment by 2 or 9, and challenge with 2.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Wilson, William Chauncey

• Health Sciences, Toxicology
• Health Sciences, Pharmacology

Identifier

(UMI)AAI8603296

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/70033