Interleukins-12 and -23 do not alter expression or activity of multiple cytochrome P450 enzymes in cryopreserved human hepatocytes.
Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of IL-12 and IL-23. Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon α-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor-α) or known P450 inducers (β-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL-23 to directly alter P450 enzymes in human hepatocytes.
Drug Metabolism and Pharmacokinetics, Janssen Research & Development, LLC, 1000 Route 202 South, Room B104A, Raritan, NJ 08869, USA. sdallas@its.jnj.com
Shannon
S
Dallas
Souvik
S
Chattopadhyay
Carlo
C
Sensenhauser
Ameesha
A
Batheja
Monica
M
Singer
Jose
J
Silva
D002097:C-Reactive Protein / Q000096:biosynthesis; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D053759:Interleukin-23 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000187:drug effects; D053707:Receptors, Interleukin-12 / Q000096:biosynthesis / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000494:pharmacology
C515500:IL23R protein, human; D053759:Interleukin-23; D015850:Interleukin-6; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D019324:beta-Naphthoflavone; D002097:C-Reactive Protein; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin; D010634:Phenobarbital