1: Arch Toxicol.  2004 Mar;78(3):131-8. Epub 2003 Nov 05. 

Age-related changes in the protein and mRNA levels of CYP2E1 and CYP3A isoforms
as well as in their hepatic activities in Wistar rats. What role for oxidative
stress?

Wauthier V, Verbeeck RK, Buc Calderon P.

Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie (PMNT),
Departement des sciences pharmaceutiques, Universite Catholique de Louvain,
Avenue E. Mounier 73, 1200, Brussels, Belgium.

Drug biotransformation and its therapeutic effect may be modified during ageing.
Among different causative factors of ageing, the impairment of normal cellular
functions by free radicals has been evoked as playing a critical role. The
effect of age on the expression and activity of CYP2E1 and CYP3A was
investigated in male Wistar rats of 3, 8, 11 and 18 months old. The total
cytochrome P450 as well as the expression and the activity (midazolam oxidation)
of CYP3A isoforms did not change until 18 months of age. Chlorzoxazone
hydroxylation (CYP2E1 activity) increased from 3 to 8 months, remained constant
between 8 and 11 months and then progressively decreased until 18 months.
Interestingly, CYP2E1 microsomal protein followed the same enzyme activity
profile from 3 to 8 months, but remained constant thereafter. The level of
CYP2E1 mRNA did not change over the whole period. While the amount of proteins
did not change after 8 months, their functionality may be affected by oxidative
stress (increase in thiobarbituric acid reactive substances, decrease in reduced
glutathione level). However, no changes in carbonyl protein content were
observed. The decrease in CYP2E1 activity in rats after 11 months is most
probably due to post-translational modifications of CYP2E1 proteins. Indeed, it
may be correlated with an accumulation of oxidative damage. Since no change was
observed in CYP3A activity or in their protein and mRNA content, it seems that
such isoforms should be less affected by oxidative stress.

PMID: 14600803 [PubMed - in process]