Table 3.
Gene-markers of hepatotoxicity affected by CBD administration. Genes that are significantly up- or down-regulated sorted by greatest fold changed at the highest dose (2460 mg/kg or MED of 200 mg/kg). Cells in bold italics indicate those significantly different from vehicle (One-Way ANOVA, indicated by *, or Kruskal-Wallis test with appropriate post-hoc comparison). Genes that are commonly and significantly dysregulated in both the acute and sub-acute studies are highlighted in yellow. Data presented as mean ± SEM (n = 6/group) fold change from vehicle.
| Up-Regulated | ||||||
| Single Dose | 2 Week Dosing | |||||
| Gene | 246 mg/kg | 738 mg/kg | 2460 mg/kg | 61.5 mg/kg | 184.5 mg/kg | 615 mg/kg |
| Krt8 | 32.6 ± 18.5 | 32.2 ± 0.4 | 46.9 ± 25.1 | 0.7 ± 0.1 | 0.8 ± 0.2 | 8.7 ± 4.2 * |
| Map3k6 | 4.9 ± 1.9 | 1.6 ± 0.2 | 38.0 ± 17.3 | 1.7 ± 0.9 | 0.8 ± 0.1 | 8.6 ± 2.9 |
| Cdkn1a | 0.3 ± 0.1 | 0.5 ± 0.2 | 22.7 ± 6.9 | 0.3 ± 0.1 | 0.4 ± 0.1 | 9.3 ± 3.7 |
| Hmox1 | 0.9 ± 0.1 | 2.8 ± 0.6 | 19.0 ± 8.8 * | 1.5 ± 0.4 | 1.5 ± 0.3 | 2.4 ± 1.2 |
| Nqo1 | 3.6 ± 0.8 | 4.92 ± 1.0 * | 9.7 ± 1.7 * | 1.0 ± 0.1 | 1.1 ± 0.1 | 6.2 ± 1.2 * |
| Ugt1a1 | 4.8 ± 0.5 | 7.8 ± 0.6 | 7.5 ± 1.0 | 2.7 ± 0.1 | 4.1 ± 0.2 | 9.1 ± 0.9 |
| Rplp2 | 1.0 ± 0.1 | 1.5 ± 0.2 | 5.7 ± 0.8 * | 0.5 ± 0.1 | 0.5 ± 0.1 | 0.7 ± 0.2 |
| Abcb1a | 1.5 ± 0.4 | 1.0 ± 0.2 | 5.6 ± 0.8 | 2.1 ± 0.5 | 2.1 ± 0.2 | 6.4 ± 1.8 * |
| Slc39a6 | 2.0 ± 0.3 | 1.4 ± 0.1 | 5.5 ± 1.3 | 1.1 ± 0.2 | 0.9 ± 0.1 | 2.9 ± 1.1 |
| Aldoa | 2.8 ± 0.9 | 2.1 ± 0.2 | 5.4 ± 1.4 | 1.3 ± 0.1 | 1.1 ± 0.1 | 2.8 ± 0.5 * |
| Pla2g12a | 1.6 ± 0.3 | 2.0 ± 0.3 | 5.3 ± 0.6 | 1.7 ± 0.3 | 1.4 ± 0.1 | 3.5 ± 0.3 |
| Ubc | 1.3 ± 0.1 | 1.1 ± 0.2 | 4.8 ± 0.6 * | 0.6 ± 0.1 | 1.1 ± 0.1 | 1.6 ± 0.3 |
| Abcc3 | 2.6 ± 0.6 | 2.4 ± 0.4 | 4.5 ± 1.2 | 1.2 ± 0.2 | 1.1 ± 0.1 | 2.2 ± 0.3 * |
| Abcc2 | 1.4 ± 0.2 | 1.6 ± 0.3 | 3.9 ± 0.3 * | 1.2 ± 0.1 | 0.9 ± 0.0 | 3.4 ± 1.3 |
| Gsr | 1.9 ± 0.5 | 2.7 ± 0.3 * | 3.9 ± 0.4 * | 0.8 ± 0.1 | 0.9 ± 0.1 | 2.9 ± 0.5 * |
| Icam1 | 1.9 ± 0.4 | 1.2 ± 0.2 | 3.8 ± 0.9 | 0.8 ± 0.1 | 0.7 ± 0.1 | 1.9 ± 0.6 |
| Cyp3a11 | 2.9 ± 0.3 * | 1.6 ± 0.2 | 3.6 ± 0.7 * | 2.3 ± 0.2 * | 1.6 ± 0.2 | 2.9 ± 0.3 * |
| Txnrd1 | 1.3 ± 0.2 | 1.6 ± 0.3 | 3.5 ± 0.4 | 1.4 ± 0.3 | 1.0 ± 0.2 | 2.6 ± 1.0 |
| Lss | 3.2 ± 0.5 | 2.2 ± 0.1 | 0.3 ± 0.0 | 0.5 ± 0.2 | 0.4 ± 0.2 * | 0.9 ± 0.7 |
| Pgk1 | 1.7 ± 0.4 | 1.3 ± 0.1 | 3.1 ± 0.9 | 0.9 ± 0.0 | 1.0 ± 0.1 | 1.6 ± 0.3 |
| Ddx39 | 1.1 ± 0.1 | 2.2 ± 0.6 * | 2.6 ± 0.3 * | 0.9 ± 0.1 | 0.6 ± 0.1 | 3.1 ± 0.7 |
| Psme3 | 1.2 ± 0.2 | 1.0 ± 0.1 | 2.6 ± 0.5 | 1.0 ± 0.1 | 0.8 ± 0.1 | 1.5 ± 0.3 |
| Ipo4 | 1.1 ± 0.1 | 1.9 ± 0.3 * | 2.5 ± 0.2 * | 0.8 ± 0.1 | 0.9 ± 0.1 | 1.7 ± 0.4 |
| Osmr | 1.4 ± 0.2 | 1.0 ± 0.2 | 2.4 ± 0.3 * | 0.7 ± 0.1 | 0.4 ± 0.1 | 1.5 ± 0.6 |
| Krt18 | 1.5 ± 0.2 | 2.0 ± 0.2 * | 2.2 ± 0.4 * | 0.7 ± 0.1 | 0.7 ± 0.1 | 3.2 ± 0.9 |
| Timm10b | 1.3 ± 0.1 | 1.7 ± 0.2 * | 1.9 ± 0.3 * | 1.0 ± 0.1 | 1.1 ± 0.2 | 1.7± 0.4 |
| Tfrc | 2.0 ± 0.1 | 3.3 ± 0.6 | 1.8 ± 0.1 | 1.3 ± 0.1 | 0.7 ± 0.1 | 2.6 ± 0.3 * |
| Mrps18b | 0.8 ± 0.0 | 0.9 ± 0.1 | 1.7 ± 0.2 * | 1.0 ± 0.1 | 0.8 ± 0.1 | 1.6 ± 0.3 |
| Down-Regulated | ||||||
| Single Dose | 2 Week Dosing | |||||
| Gene | 20 mg/kg | 60 mg/kg | 200 mg/kg | 5 mg/kg | 15 mg/kg | 50 mg/kg |
| Igfals | 1.1 ± 0.1 | 0.5 ± 0.1 * | 0.02 ± 0.0 * | 0.8 ± 0.1 | 0.9 ± 0.2 | 0.2 ± 0.1 * |
| Lgr5 | 1.2 ± 0.1 | 0.5 ± 0.1 * | 0.04 ± 0.0 * | 0.4 ± 0.0 * | 0.3 ± 0.1 * | 0.2 ± 0.0 * |
| Car3 | 0.8 ± 0.1 | 0.2 ± 0.0 * | 0.1 ± 0.1 * | 0.5 ± 0.1 * | 0.5 ± 0.0 * | 0.1 ± 0.0 * |
| Atp8b1 | 1.4 ± 0.3 | 0.5 ± 0.1 | 0.2 ± 0.0 | 0.6 ± 0.1 | 0.5 ± 0.1 | 0.4 ± 0.1 |
| Ppara | 0.7 ± 0.1* | 0.6 ± 0.0 * | 0.2 ± 0.0 * | 0.5 ± 0.1 * | 0.5 ± 0.1 * | 0.3 ± 0.1 * |
| Avpr1a | 1.1 ± 0.2 | 0.8 ± 0.1 | 0.2 ± 0.0 * | 0.5 ± 0.1 * | 0.3 ± 0.1 * | 0.3 ± 0.1 * |
| Abcb11 | 1.1 ± 0.2 | 0.5 ± 0.0 * | 0.2 ± 0.0 * | 0.6 ± 0.1 | 0.7 ± 0.1 | 0.3 ± 0.1 * |
| Mcm10 | 1.9 ± 0.5 | 1.4 ± 0.1 | 0.2 ± 0.0 | 0.9 ± 0.2 | 0.6 ± 0.1 | 0.2 ± 0.0 * |
| Fabp1 | 0.6 ± 0.0 * | 0.4 ± 0.0 * | 0.2 ± 0.1 * | 0.8 ± 0.1 | 0.7 ± 0.0 * | 0.1 ± 0.0 * |
| Fads1 | 0.7 ± 0.1 | 0.6 ± 0.0 | 0.2 ± 0.0 | 0.9 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.2 |
| Cdc14b | 0.9 ± 0.1 | 0.7 ± 0.1 | 0.3 ± 0.0 | 0.6 ± 0.1 * | 0.7 ± 0.1 | 0.4 ± 0.1 * |
| Mbl2 | 1.3 ± 0.1 | 0.7 ± 0.0 | 0.3 ± 0.0 * | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.6 ± 0.1 * |
| Asah1 | 1.1 ± 0.1 | 0.9 ± 0.1 | 0.4 ± 0.1 * | 0.8 ± 0.1 | 0.7 ± 0.1 | 0.6 ± 0.1 |
| Lpl | 0.7 ± 0.0 | 0.4 ± 0.1 | 0.5 ± 0.1 | 0.4 ± 0.1 | 0.5 ± 0.1 | 0.2 ± 0.1 |
| Emc9 | 1.3 ± 0.2 | 0.7 ± 0.0 | 0.5 ± 0.0 | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.6 ± 0.1 |
| Rhbg | 0.9 ± 0.1 | 0.5 ± 0.0 * | 0.5 ± 0.1 * | 0.7 ± 0.1 | 1.0 ± 0.1 | 0.6 ± 0.2 |
| L2hgdh | 0.9 ± 0.1 | 0.8 ± 0.0 | 0.5 ± 0.1 * | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.4 ± 0.1 * |
| Cxcl12 | 1.2 ± 0.2 | 0.8 ± 0.1 | 0.5 ± 0.1 | 0.8 ± 0.0 | 0.7 ± 0.0 * | 0.4 ± 0.1 * |
| Maob | 1.0 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.0 * | 0.8 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.1 * |
| Rdx | 1.1 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.0 * | 0.7 ± 0.1 | 0.8 ± 0.1 | 0.7 ± 0.1 |
| B2m | 1.0 ± 0.1 | 0.6 ± 0.0 * | 0.7 ± 0.1 | 0.9 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.1 * |
| Cryl1 | 1.0 ± 0.2 | 0.4 ± 0.0 | 0.7 ± 0.1 | 0.8 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.1 |
| Ipo8 | 1.4 ± 0.1 | 0.8 ± 0.1 * | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.7 ± 0.1 | 0.5 ± 0.2 * |
| Srebf1 | 1.2 ± 0.1 | 0.7 ± 0.1 | 0.9 ± 0.1 | 0.8 ± 0.1 | 0.7 ± 0.1 | 0.7 ± 0.1 * |
| Scd1 | 0.6 ± 0.1 | 0.3 ± 0.0 * | 0.9 ± 0.3 | 0.5 ± 0.1 | 0.6 ± 0.0 | 0.1 ± 0.0 |
| Dnajb11 | 1.3 ± 0.2 | 1.1 ± 0.1 | 1.1 ± 0.2 | 0.7 ± 0.1 | 0.4 ± 0.1 * | 0.9 ± 0.1 |
| Tagln | 1.0 ± 0.1 | 0.8 ± 0.2 | 1.2 ± 0.7 | 0.6 ± 0.1 | 0.5 ± 0.1 * | 0.3 ± 0.1 * |
| Abcb4 | 1.1 ± 0.3 | 0.6 ± 0.1 | 1.4 ± 0.4 | 0.8 ± 0.1 | 0.6 ± 0.1 | 0.4 ± 0.1 * |
| Fasn | 2.2 ± 0.3 | 1.4 ± 0.1 | 1.5 ± 0.5 | 0.5 ± 0.0 | 0.4 ± 0.1 * | 0.5 ± 0.2 |