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These data show that adiponectin may have a role in the pathogenesis of human NASH and should be investigated further.

ABSTRACT:Cytochrome P450 2C9-mediated metabolism has been shown to be activated in the presence of the effector dapsone. However, it has yet to be established what effector structural features are necessary to activate CYP2C9 activity. To address this question, kinetic studies were conducted with nine analogs of dapsone containing various functional properties (three sulfone compounds, three carbonyl compounds, and three sulfonamide compounds), to examine the functional groups important for enzyme activation by the effector (dapsone). Results show that phenylsulfone (dapsone without the paraamino groups) activates flurbiprofen 4-hydroxylation comparable to dapsone but inhibits naproxen demethylation. Meanwhile, p-tolylsulfone had little effect on flurbiprofen metabolism, but activated naproxen demethylation, albeit only at high concentrations. These substrate-dependent differences in effect suggest that naproxen has a different binding orientation compared with flurbiprofen. Perhaps most interesting is that replacement of only one amino group from dapsone with a nitro group (4-(4-nitrophenylsulfonyl)-aniline) resulted in substantial inhibition of flurbiprofen 4-hydroxylation, suggesting that electronic effects may influence activation of this substrate. Other analogs either had minor or no effect on CYP2C9-mediated metabolism. Overall, it is apparent from these studies that a sulfone group in direct association with two benzene rings with paraelectron-donating groups represents the most efficient activator of CYP2C9. However, the effects of these analogs appear to be concentration-and substrate-dependent, further complicating the prediction of these types of in vitro interactions.Cytochrome P450 (P450 1 ) enzymes are a superfamily of enzymes responsible for metabolizing a wide range of endogenous and xenobiotic compounds (Wrighton and Stevens, 1992;Guengerich, 1995). Within this superfamily, CYP2C9 is known to be an important isoform responsible for metabolizing many relevant compounds such as (S)-warfarin (Rettie et al., 1992), phenytoin and tolbutamide (Veronese et al., 1991), as well as many nonsteroidal anti-inflammatory drugs (Miners and Birkett, 1998). Consequently, factors that modulate the activity of this enzyme are of substantial interest to the drug industry, as well as to academic scientists, since the resultant effects may alter a drug's therapeutic efficacy or toxicity.Our lab has determined that CYP2C9 often does not follow normal Michaelis-Menten kinetics. For example, CYP2C9-mediated flurbiprofen 4Ј-hydroxylation has been shown to be activated by the effector dapsone in human liver microsomes and baculovirus-expressed CYP2C9 (Korzekwa et al., 1998). In addition, kinetic studies on the activation of flurbiprofen 4Ј-hydroxylation, as well as naproxen demethylation by dapsone have recently been reported (Hutzler et al., 2001). Data from this kinetic study were fit to a two-site effector model equation that resulted in an increase in the V max and a decrease in the K m parameter estimates for the me...

Baseline intestinal activity of CYP3A4 was a key determinant of variability of the inhibitory effect of clarithromycin among individuals. CYP3A5*1 alleles were associated with greater baseline intestinal CYP3A activity and, therefore, greater extent of inhibition. The primary in vivo mechanism was not rapidly reversible competitive or irreversible inhibition but was likely formation of metabolic intermediate complexes.