Todd spent the 1997-98 year on sabbatical in the Department of Pharmaceutics at the University of Washington. During the sabbatical he conducted research on the regulation of cytochrome P450 2E1 (CYP2E1) in the laboratory of Professor John Slattery.

CYP2E1 is a constitutive enzyme involved in the oxidation of endogenous substrates and xenobiotics. CYP2E1 is induced by a variety of physiologic conditions, including birth, starvation, obesity and diabetes, as well as by the action of chemical agents. Unlike other P450s, the induction of CYP2E1 by xenobiotics occurs via ligand stabilization of the protein, rather than by enhanced de novo synthesis. Ligand binding protects the enzyme from degradation, resulting in accumulation of the protein via normal biosynthetic mechanisms.

Degradation of CYP2E1 in vivo has been observed to by biphasic, with a rapid turnover half-life of seven hours and a slow turnover half-life of about 40 hours. Treatment of rats with CYP2E1 inducing agents (acetone, ethanol, isoniazid) abolishes the rapid turnover phase, and elimination of CYP2E1 becomes monophasic with a half-life of 40 hours. Induction of CYP2E1 by these agents is attributed to their inhibition of the fast degradation phase.

The biphasic degradation of CYP2E1 suggests that degradation occurs in two kinetically separate pools, either chemically or physically distinct. Since chemically different forms of CYP2E1 that retain catalytic competence are unknown, the existence of two physically distinct pools of CYP2E1 is more likely. An obvious possibility for the sites of two physically distinct pools of CYP2E1 in hepatic tissue would be their localization within the smooth and the rough endoplasmic reticulum.

Dr. Cochran's current research encompasses investigation of smooth and rough endoplasmic reticulum as the loci of the two kinetic pools for CYP2E1 degradation.