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We examined the effects of model activators of mitogen-activated protein kinases (MAPKs) on basal and rifampicin-, phenobarbital- and dioxin-inducible expression of phase I and phase II biotransformation enzymes in primary human hepatocytes. Cells were treated for 24 h with sorbitol (SOR), anisomycin (ANI) and epidermal growth factor (EGF) in the presence or absence of inducers. The levels of CYP1A1, CYP1A2, CYP2B6, CYP3A4, UGT1A1, UGT2B17, SULT1A1, SULT2A1, SULT1B2, GSTA1, GSTA2 mRNAs were determined. SOR and EGF inhibited the expression of the tested genes, while ANI had no effect. We conclude that MAPKs play important role in the transcriptional regulation of drug-metabolizing enzymes.

Mitogen-activated protein kinases (MAPKs) are important regulators of aryl hydrocarbon receptor (AhR). An immense progress in MAPKs' biochemistry was attained with the discovery of their specific pharmacological inhibitors. Unfortunately, the inhibitors of JNK and ERK MAPKs, i.e. SP600125 and U0126, respectively, affect AhR-CYP1A signaling pathway because they are partial agonists of AhR and induce CYP1A genes. This implies that SP600125 and U0126 are inappropriate tools for studies of the role of MAPKs in AhR regulation. The results from studies using SP600125 or U126, past or future, should be interpreted with prudence regarding their stimulatory effects on AhR-CYP1A pathway.

We investigated the effects of novel microtubules interfering agents (MIAs) in primary cultures of rat hepatocytes. Cells were treated for 24 h with a known compound colchicine and newly synthesized derivatives myoseverin, tubulyzine, and E2GG. We examined the effects of MIAs on microtubules network integrity and on the polymerization capability of isolated tubulin. All tested MIAs inhibited microtubules assembly with the following IC(50) values: tubulyzine (4.4 + or - 0.9 micromol/l), myoseverin (7.0 + or - 0.8 micromol/l), E2GG (16 + or - 2 micromol/l), colchicine (2.0 + or - 0.4 micromol/l). The potency of MIAs to perturb microtubular network integrity (monitored by immune-histochemistry) increased in the order tubulyzine < myoseverin < E2GG < colchicine. We described recently deleterious effects of MIAs on the expression of drug metabolizing enzymes, including CYP1A1. Here we observed inhibitory effects of novel MIAs on dioxin-inducible expression of CYP1A1 mRNA in rat hepatocytes. We conclude that novel MIAs exert analogical biological response as classical MIAs such as colchicine or nocodazole. This further supports the hypothesis that tubulin is the primordial target of MIAs within the cell and that perturbation of microtubules dynamics and/or integrity triggers the biological effects described here.

In the present work, the effects of colchicine (COL) and/or all-trans retinoic acid (ATRA) on expression of rexinoid receptors (RXRs) (alpha, beta, gamma), thyroid hormone receptor alpha and coregulators N-CoR, SMRT and SRC-1 mRNA in primary rat hepatocytes as a model of no-proliferating cells were investigated. Treatment with these components, either alone or in combination, induced differences of the expression profiles between distinct treatment groups.