Considerations for use of recombinant adenoviral vectors: dose effect on hepatic cytochromes P450.

Recombinant adenovirus (Ad) serotype 5 is a vector commonly used for gene delivery. Although this vector has a natural tropism for the liver, there is a limited understanding of how Ad administration affects one of the primary hepatic processes, drug metabolism. The effects of systemic administration of a model recombinant adenoviral vector on two hepatic cytochrome P450 (P450) enzymes, CYP3A2 and 2C11, were investigated.

Cyclosporine and bromocriptine-induced suppressions of CYP3A1/2 and CYP2C11 are not mediated by prolactin.

The purpose of this study was to determine if the suppression of hepatic CYP3A1/2 (cytochrome P450 3A1/2) and CYP2C11 (cytochrome P450 2C11) by cyclosporine is mediated by prolactin. Male intact rats were given subcutaneous doses of either 15 mg/kg/day of cyclosporine or 1 ml/kg/day of cyclosporine vehicle concomitantly with one of the following: 500 mg/kg prolactin, 1 ml/kg prolactin vehicle, 4 mg/kg bromocriptine, or 1 ml/kg bromocriptine vehicle for 14 days. Protein expressions were measured using Western blot analysis and activities were measured using an in vitro testosterone hydroxylation assay.

The effect of lipoprotein-associated cyclosporine on drug metabolism and toxicity in rats.

Purpose: The objective of the study was to examine the effect of lipoprotein-associated cyclosporine on hepatic metabolism, hepatic lipoprotein receptors, and renal toxicity in comparison to the current commercially available cyclosporine (CSA) product.

Methods: Rats within the same group were given one of the following treatments: 10 mg/kg of CSA, plasma-CSA, very low-density lipoprotein (VLDL)-CSA, low-density lipoprotein (LDL)-CSA, LDL, high-density lipoprotein (HDL)-CSA, 1 mL/kg of vehicle, or saline intravenously for 14 days. Urine and blood samples were evaluated for renal function.

Suppression of hepatic CYP3A1/2 and CYP2C11 by cyclosporine is not mediated by altering growth hormone levels.

Cyclosporine (CsA) suppresses drug metabolism by decreasing cytochrome P450 (P450) enzyme levels in rat liver. Growth hormone (GH) is known to pretranslationally regulate P450 expression. Thus, the suppression of P450 by CsA may involve GH as an intermediate.

Altered cytochrome P450 and P-glycoprotein levels in rats during simulated weightlessness.

Background: In order to investigate the effects of simulated weightlessness on drug metabolism, liver, kidney, and small intestine, microsomal proteins from tail-suspended rats were analyzed to determine cytochrome P450 (CYP) and P-glycoprotein levels following varying durations of tail-suspension.

Hypothesis: P-glycoprotein and CYP levels would both decrease similar to previous findings from actual spaceflight data.

Methods: Six groups of four Sprague-Dawley rats each were tail-suspended for up to 21 d; CYP and P-glycoprotein levels in the liver, kidney and small intestine were then measured by Western blotting.