I needed to disable self sign-ups because I’ve been getting too many spam-type accounts. Thanks.
Protective Effects of Citral
We have been eating several slices of lemon every morning because it is an easy to find fruit and it is low vitamin A. This discussion is interesting. Sometimes I eat a small portion of the peel.
Today I purchased some Cymbopogon flexuosus oil at the pharmacy, which is marketed for topical application (and there is a warning against systemic administration). The main components are (E)-citral 33.1%; (Z)-citral 30%; geranyl acetate 12%; geraniol 5%; citronellyl acetate 4.2%; linalool 2.6%; limonene 2% (Chowdhury, Tandon et al. 2010).
According to safety data sheets, the LD50 for the other components is geranyl acetate 6.3 g/kg; geraniol 3.6 g/kg; citronellyl acetate 6.8 g/kg; linalool 2.8 g/kg; limonene 5.3 g/kg. From a further cursory investigation of the remaining components I didn’t immediately see any other substances that could cause injury or death at the doses in question. Additionally, in the safety data sheet for Cymbopogon citratus oil the LD50 is given as 4.4 g/kg (for comparison, the LD50 for retinol is 2 g/kg).
According to (Gonçalves, Assis et al. 2020), while 50 mg/kg I.V. was the dose most studied in rats, 100 mg/kg appeared more effective than 50 mg/kg and 300 mg/kg in the treatment of carrageenan-induced thermal allodynia. Notably, area under curve (AUC) in the time interval of 15–240 min after administration was lower in the 100 mg/kg group than in the 50 mg/kg or 300 mg/kg groups which is unusual. Additionally, doses up to 300 mg/kg produced no apparent toxicity symptoms while doses of 1,000 mg/kg and 2000 mg/kg resulted in a reduction in locomotion, touch sensitivity and respiratory movement lasting 24 and 72 hours, respectively. The oral bioavailability was recently reported as 100% and metabolites included a number of acids and a single bilary glucuronide (Sharma, Habib et al. 2021).
Since I weigh around 150 lbs, my goal is to administer a one-time dose of 7 g (102.9 mg/kg) and then observe whether a) there is some kind of effect and b) whether elimination appears to follow first-order kinetics or whether a deep compartment model is applicable like for retinoids. According to (Baker 2018) the density is 0.895–0.906, indicating that the 5 mL bottle I bought contains 4.475–4.53 g, or about 2.824–2.858 g citral, which I guess will have to do for now. Since the recommended dosage for topical application is 15 drops (0.75 mL), my regimen will be as follows:
- Allergy test 1 drop (about 45 mg or 28.4 mg citral)
- After 1 week: allergy test 15 drops (about 675 mg or 426 mg citral)
- After 2 weeks: the remaining 4.2 mL (about 3.78 g or 2.39 g citral)
As a carrier I’ll likely use a tablespoon of olive oil. If I don’t notice any adverse effects I might try higher doses later. I’m not sure whether lemons or lemonade would produce any effects, since as we’ve seen here the required dosages seem to be quite high.
Quote from ggenereux on August 14, 2021, 10:12 amI find it interesting that the side-chain of retinol, and the interior chains in beta-carotene, turpentine, cholesterol, and steroids etc are made up of isoprene units. As is citral. So, there's a least a plausible chemical interaction between citral and vA /RA.
That’s the reason I had glossed over citral a while back, but now I’m starting to become more open to the idea that it could actually be beneficial, similar to how ethanol is used to methanol toxicity.
Quote from Даниил on August 14, 2021, 11:21 amAs far as I know, dehydrogenases and p450 work only with atra. I also don't know how effective retinol glucuronidation is. Also, it will simply be excreted with bile. But I am not sure that it will be quickly
By itself, retinol causes, at least, atherosclerosis.
You would be surprised to see just how many enzymes are capable of metabolizing retinol. HSD17B6 and DHRS9, for example, both preferentially reduce RAL to ROL at normal pH and NAD+/NADH ratio (but they eventually start oxidizing ROL after NAD+ is depleted, or at acidic pHs). I suspect many of the other SDRs also show some affinity towards ROL, but that hasn’t been demonstrated yet. CYP1A1 > CYP1A2 > CYP1B1 (ordered by most efficient at oxidizing ROL and coincidentally also by most downregulated in NAFLD) all oxidize atROL with NADP+ as co-factor. Additionally, retinoic acid was shown capable of binding to CoA (Renstrom and DeLuca 1989), and I think a very under-researched area is whether the body attempts β-oxidation of retinoyl-CoA and what the products might be.
You're right, I hadn't thought of atherosclerosis. I would imagine that the plaques eventually break down after a while on the VAD diet.
Bibliography
Baker, B. P. G., Jennifer A. (2018). "Lemongrass Oil Profile." New York State IPM Program.
Chowdhury, S. R., P. K. Tandon and A. R. Chowdhury (2010). "Chemical Composition of the Essential Oil of Cymbopogon flexuosus (Steud) Wats. Growing in Kumaon Region." Journal of Essential Oil Bearing Plants 13(5): 588-593.
Gonçalves, E. C. D., P. M. Assis, L. A. Junqueira, M. Cola, A. R. S. Santos, N. R. B. Raposo and R. C. Dutra (2020). "Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways." Journal of Natural Products 83(4): 1190-1200.
Renstrom, B. and H. F. DeLuca (1989). "Incorporation of retinoic acid into proteins via retinoyl-CoA." Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 998(1): 69-74.
Sharma, S., S. Habib, D. Sahu and J. Gupta (2021). "Chemical Properties and Therapeutic Potential of Citral, a Monoterpene Isolated from Lemongrass." Med Chem 17(1): 2-12.
Since citral was shown to be a competitive inhibitor of RDH and RALDH, it is presumably metabolized to the corresponding carboxylic acid, geranic acid, in vivo. Geranic acid, unlike retinoic acid (RA), was reported to be “slightly soluble” in water, 1.22 g/L compared to 0.0048 g/L for RA according to FooDB, and is slightly less acidic than RA (pKa = 5.26 vs 5 for RA). Additionally, unlike the biotransformation of retinal (RAL) to RA, the oxidation of (E)-citral to geranic acid is theoretically reversible and may help alleviate NAD+/NADH imbalances. Biotransformation of (Z)-citral likely yields neranic acid, which has not been studied in humans.
Geranic acid has been investigated for its penetration of bacterial biofilms, which are believed to play a role in the pathogenesis of acne (Honraet, Rossel et al. 2014). Additionally, geranic acid is a tyrosinase (TYR; 0.051; n.d.) inhibitor, which catalyzes the rate limiting step in the production of melanin from tyrosine. TYR also catalyzes the production of L-dopaquinone from the dopamine precursor L-DOPA. This would suggest that administration of citral may produce effects similar to CNS stimulants like coffee and amphetamine, and it may decrease the rate at which skin tans when exposed to sun.
Earlier today I ingested the first allergy test, which inadvertently became 2 drops, or 56.8 mg citral. I’ll report back when I take take the next allergy test, which I might do in less than the planned week because of geranic acid’s comparatively greater water solubility.
Bibliography
Honraet, K., B. Rossel and T. Coenye (2014). The Acne Biofilm. Pathogenesis and Treatment of Acne and Rosacea. C. C. Zouboulis, A. D. Katsambas and A. M. Kligman. Berlin, Heidelberg, Springer Berlin Heidelberg: 155-159.
@johannes2, I've posted a couple of videos by a video blogger called chubbyemu. If I've learned one thing from his videos, its that you can get yourself into big trouble faster than you realize.
I watched one yesterday that reminded me of a thing I did to myself a few years back. The video was about a guy who ate loads of liqorice. It led to a fatal heart attack because the licorice caused all the potatssium to exit his muscles and be replaced with salt. I thought that my adrenal was burned out, and read that licorice was helpful. I began taking a lot of it, and ended up on the couch with two massively swollen feet. Who knows, if I'd not been allowed to rest on the couch, and instead had a tough job (like the man in the video) maybe I'd be dead now.
Word to the wise: plant poisons can kill. *Sometimes*, in tiny amounts, (perhaps over a long time) they *might* help. It's the dose that makes the poison. Plants make these chemicals to kill bugs, these are weapons. VA isn't the only plant poison in town.
@johannes2 Any news with your citral experiment? I wish you well!
Hey everyone, I’m still conducting the experiment but I’ve been a bit hesitant to post the results for reasons given below. About two weeks ago I ingested the second allergy test of 4 drops, which should amount to 180 mg oil or 113 mg citral. To provide some context, I’m 23 years old, male, and affected by acne. Here’s what I wrote at the time: “Four drops in a tablespoon of olive oil produced a burning sensation in my mouth similar to Nicorette gum, not entirely unpleasant and with a lemony taste. After waking up this morning (about 15 hours since citral administration), I noticed an improvement in my skin with a visible reduction in inflammation. Notably, my feet which are usually a little red due to severe sunburn years ago (while on Accutane) are normally colored. Redness around my fingernails, especially my thumbs, has also decreased. However, I can’t say with certainty that these effects are due to the citral and not because of something else. Yesterday was the first after a few days of driving for extended periods of time, so it could have also simply been decreased stress.”
A week ago I undertook the ultimate stress test by eating a large pizza from Pizza Hut. Whereas I normally sleep about 5–6 h before waking up, after eating the pizza I slept for about 8 h and woke up feeling terrible, with a “Vitamin A hangover” similar to those produced by alcohol. I proceeded to ingest another 4 drops of citral, this time leaving them in my mouth for a few seconds before swallowing to allow diffusion and absorption, and to prevent the citral from possibly being damaged during digestion. I was very surprised when within seconds most aspects of the “hangover” appeared to disappear, notably the brain fog, lack of energy and motivation. I have never experienced such a rapid effect with any non-psychoactive drug, and even psychoactive drugs normally produce more feelings of intoxication than of rapid symptom relief.
The next day, I undertook another stress test by eating Taco Bell (where the cheese contains large amounts of added beta carotene), this time ingesting the citral directly after the meal. This time the effects were not as pronounced, almost indistinguishable from placebo, and my digestive system and energy were affected by the meal for a few hours.
Research-wise, I didn’t find much new information, however I remember reading a study in which citral was tested on humans and the dose given was 150 mg. Unfortunately I can’t seem to find the study now, but for that reason I’ve determined to not increase the dosage to more than 4–5 drops at a time.
While my personal results appear promising, I did come across quite a few studies using human cell lines (HepG2 liver cells and leukocytes), and citral apparently produced both cytotoxicity and genotoxicity (Souza, Silva et al. 2020). For that reason, I do not suggest anyone try supplementing citral unless they are aware that it could damage certain cells and that it could lead to the formation or proliferation of cancers. Additionally, citral is reportedly very effective topically, so that might be a safer option than systemic administration in certain skin diseases (maybe someone familiar with traditional medicine could try this). I’m personally not discouraged by these studies, as there could be a number of explanations for the results, most importantly the concentration. Since it diffuses so easily (like vitamin A), wherever it ends up in the body it will spread out rapidly, thereby possibly preventing the accumulation of concentrations great enough to cause toxic effects. Personally, I’ll keep taking citral not more often than once weekly (even though its effects appear to wear off after a day or two), four drops as needed on low energy days, but again, I do not suggest that anyone else try this.
Bibliography
Souza, A. C. S., L. K. Silva, T. B. Queiroz, E. S. Marques, C. A. Hiruma-Lima, I. O. M. Gaivão and E. L. Maistro (2020). "Citral presents cytotoxic and genotoxic effects in human cultured cells." Drug Chem Toxicol 43(4): 435-440.
Update on lemon juice usage
For the past 2 weeks or so, I had been drinking about 2 tablespoons (half of a lemon) of fresh lemon juice in the morning, shortly after rising.
I took a few days off this week and continued today to confirm
What I can report is that shortly after drinking lemon juice, I get a similar, but less intense, feeling to drinking coffee. A feeling of intoxication, sleepiness and uneasiness. It doesn't last as long but it is noticeable.
I've tried diluted lemon juice and lemon juice with baking soda with same results.
I did some more research on citral, using the very useful SwissTargetPrediction.ch, which predicts possible molecule-protein-interactions, and SwissADME.ch, which predicts certain pharmacokinetic parameters including lipophilicity and whether a molecule can cross the blood-brain-barrier (BBB). For some genes, I looked up their expression in NAFLD, and the two numbers in parentheses following a gene symbol—for example “GLI1 (0.239; 1.145)”—denote the log2 fold change of the gene in NAFLD hepatocytes compared to control as determined by (Wruck and Adjaye 2017) and (Hoang, Oseini et al. 2019).
(E)-citral (geranial) may interact with (5% probability) ALDH1A1, GLI2, GLI1, (4% probability) CHRM2, CHRM1, CHRM3, MAOA, CYP2A6, SRD5A1, ADH1A, ADH1B, ADH7, MAOB, (DBF4, CDC7), ADH4, ADH1C, (CCND1, CDK4), CYP2C19, MTNR1A, MTNR1B and DRD2.
(Z)-citral (neral) may interact with (6% probability ) ADH1A, (5% probability) ALDH1A1, DRD2, (4% probability ) DRD4, PDE7A, CHRM2, CHRM1, CHRM3, MAOA, MAOB, SIRT2, GLI2, GLI1, TYMS, IMPDH2, PARP1, CYP2A6, CHRM4, CHRM5, KAT2B, CYP2C19, SRD5A1, GSR, ADH1C, CTSK, CTSL, CTSB, TDO2, IDO1, (CHRNA4, CHRNB2), PTGS2, ADH1B, ADH7, CA2, CA1, ACHE, PIN1, MPO, CHEK1, CA5A, (GABRB3, GABRA3, GABRG2), (GABRB3, GABRG2, GABRA1), (GABRB3, GABRG2, GABRA5), (GABRA2, GABRB3, GABRG2), (GABRG2, GABRB3, GABRA6) and PABPC1.
(E)-citral and (Z)-citral have lipophilicity comparable to retinoyl β-glucuronide (2.88 vs. 2.95 WLOGP) but have a membrane permeability equal to retinal (TPSA = 17.07 Å2). (E)-citral is likely metabolized by ADH1A1 whereas (Z)-citral is likely metabolized by ADH1A. Both may interact (6% probability) with zinc finger proteins GLI1 (0.239; 1.145) and GLI2 (0.055; 0.262), which act as transcriptional activators and mediate signaling through sonic hedgehog in the hedgehog signaling pathway.
Rats exposed to high doses (1,000 mg/kg) of citral exhibited a reduction in locomotion and respiratory movement, which may be caused by citral’s possible interaction (4% probability) with the muscarinic acetylcholine receptors M1–M3 for (E)-citral, and additionally M4–M5 for (Z)-citral, of which CHRM1 (-0.222; n.d.), CHRM2 (0.009; 0.47) and CHRM5 (-0.164; -0.29) are affected in NAFLD. The M3 receptor agonist pilocarpine is used to reduce pressure inside the eye and to treat dry mouth and can cause vasodilation, whereas the nonspecific antagonist scopolamine can cause increased heart rate and dry mouth. Acycloretinal (a possible metabolite of lycopene) may interact (10% probability) only with CHRM1.
Citral may be psychoactive, as citral and its carboxylic acids, but not the carboxylic acid glucuronates are predicted to permeate the blood-brain-barrier. (E)- and (Z)-citral may interact (4% probability) with MAOA and MAOB enzymes, possibly as inhibitors (similar to MAOIs), since citral has been used in traditional medicine as a treatment for depression and is apparently effective (Agatonovic-Kustrin, Kustrin et al. 2020). Interestingly, I had taken Concerta (methylphenidate) concomitantly with citral, which should have caused serious side effects if citral is indeed an MAO inhibitor. Observed anti-depressant effects could also be explained by interactions (4% probability) of (Z)-citral, but not (E)-citral, with various GABA receptor subunits, which are also the targets of anxiolytic drugs like diazepam.
Citral may be (4% probability) metabolized by CYP2A6, for which many carcinogens, some toxins and nicotine are substrates, which supports the theory that citral is genotoxic; and by CYP2C19 (-0.94; -1.827), which epoxygenates fatty acids and may be responsible for oxidizing RA to 5,6-epoxy-RA. If CYP2C19 epoxygenates geranic/nerolic acid, it would likely do so at the 6,7 position (which was attempted during the design of novel fungicides) yielding what I think would be (2E)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enoic acid [SMILES = C\C(CCC1OC1(C)C)=C/C(O)=O] and what I will be referring to as 6,7-epoxy-GA.
6,7-epoxy-GA is not very lipophilic (WLOGP = 1.97), very soluble in water (2.59 mg/ml), has the same membrane permeability as 5,6-epoxy-RA-β-glucuronide (TPSA = 133.5), has high predicted GI absorption, is predicted to permeate the BBB, and has an 85% chance of its bioavailability being greater than 10% in rats. It may interact with (9% probability) TAS2R31, (8% probability) ATP12A, AKR1B1, ESR2, PPARG, PPARA, PTGDR2, SLC22A12 and (7% probability) ACE, REN, LTA4H, KDM2A, KMO, EGLN3, GRK2, APEX1, NOTUM, BBOX1, FOLH1, CPA3, CES2, HSP90AA1, PTGS1, OXER1, CA2, (ITGAL, ICAM1, ITGB2), MAPK10, SQLE, MME, MAOB, PTPRC, BCAT2, (SAE1, UBA2), CXCL8, HIF1A, POLA1, CSNK2A1, CSNK2A1, SLC16A1, EDNRA, GRM4, GSTA1, ACE2, GSTP1, RPS6KA5, IDE, HSPA1A, MIF, TTR, PAM, TBXA2R, POLB, KDM6B, (TAS1R3, TAS1R1), ECE1, ALPL and KDM4C. TAS2R31 is one of several bitter taste receptors and may be the receptor responsible for the taste of citrus fruits. Interestingly, there is an interaction with AKR1B, which is a family of aldehyde-reducing enzymes, of which AKR1B10 (0.837, 2.97) has recently been investigated as a biomarker for NAFLD due to its severe up-regulation. Coincidentally, AKR1B10 is also the most efficient retinal reductase (Chung, Matkowskyj et al. 2012). Peroxisome proliferator-activated receptors (PPAR) are believed to inhibit insulin responses and promote lipogenesis instead of lipid β-oxidation, indicating that citral, like retinol (via STRA6), may be lipogenic. TTR is required for plasma transportation of retinol (via ROL-RBP4-TTR complexes), so citral might competitively inhibit retinol transportation.
Geranic acid may also be hydroxylated, possibly at the 8 position to yield foliamenthoic acid [8-hydroxy-2,6-dimethyl-2,6-octadienoic acid; SMILES = C\C(CO)=C/CC\C(C)=C/C(O)=O]. Foliamenthoic acid may interact with (8% probability) UGT2B7, CDC25A and (7% probability) HSPA1A, FBP1, PIM1, PIM2, CPA1, SLC22A12, AKR1B1, COMT, ERN1, CTNNB1, AKR1C3, PARP1, CSNK2A1, CDC25B, ACE, MME, TTR, (FNTA, FNTB), (ITGAL, ICAM1, ITGB2), IDO1, REN, FOLH1 and HAO2. It is bioavailable and predicted to cross the BBB. Interestingly, of the UGT enzymes, UGT2B7 has a higher affinity for atRA than UGT1A3 (Samokyszyn, Gall et al. 2000) and is also down-regulated by both atRA and the bile acid lithocholic acid (Lu, Bratton et al. 2008). Geranic acid may also interact with UGT2B7 (13% probability). CDC25A is an oncogene which is degraded in response to DNA damage, further supporting the notion that citral is genotoxic. Apart from foliamenthoic acid, geranic acid, 13-cis-4-oxo-RA (the major metabolite of RA in intestinal and testes but not liver microsomes; 10% probability) and lycopene-5,6-diol (a possible metabolite of lycopene via reduction of lycopene-5,6-epoxide; 8% probability) also potentially interact with CDC25A.
If citral is reduced as opposed to oxidation by CYP enzymes, the resulting products would be geraniol and nerol. Geraniol may interact with (6% probability) SQLE, (5% probability) UGT2B7, JAK1, JAK2, PTGS1, PTGS2 and some other targets.
It is plausible that 4-OH-RA glucuronide (TPSA = 153.75) is more readily eliminated than retinoyl glucuronide (TPSA = 133.52), since according to Wikipedia, molecules with a TPSA > 140 tend to be poor at permeating cell membranes. Therefore, glucoronates of 6,7-epoxy-GA or foliamenthoic acid are more likely to be eliminated whereas geranoyl glucuronide [proposed SMILES: CC(C)=CCC\C(C)=C\C(=O)O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C(O)=O] likely recirculates. 6,7-epoxy-GA glucuronide [proposed SMILES: C\C(CCC1OC1(C)C)=C/C(=O)O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C(O)=O] has a predicted TPSA of 146, and may interact (9% possibility) with FDFT1, PRKCA, GLRA1, GLRA2, KCNA3, STAT3, PRKCD, PRKCB, PRKCE, PRKCH, PRKCQ, HSD11B2, HSD11B1, RORC, ATP1A1, GLI1, PLA2G1B, SQLE, PPP1CC, PPP2CA, PPP2R5A, VDR, PTPA, FOLH1, OPRK1, NAALAD2, IARS, JUN and CASP3.
Geraniol might also be esterified, even though unlike 4-oxo-RA and 5,6-epoxy-RA it was not predicted to interact with DGAT1; for example to geranyl palmitate, which may interact with (12% probability) CYP19A1 and (11.5% probability) AR, PGR, HMGCR, ATP12A, PPARG, PPARD, NR3C2, PDE4D, PLA2G4A, PRKCA, PPARA, IL1B, HSD11B1, FAAH, CDC25C, CDC25A, TTL and (FNTA, FNTB).
In conclusion, there is some evidence to suggest that citral is genotoxic, and it might produce antidepressant and anxiolytic effects through MAO inhibition, interaction with GABA receptors (for (Z)-citral) and dopamine receptors D2 (both) and D4 (only (Z)-citral). The possible interaction with UGT2B7 is concerning, since it might competitively prevent glucuronidation of retinol metabolites. Citral may also form a complex with TTR, which could competitively prevent retinol from being transported. It seems that citral inhibits different pathways both for retinoid oxidation and reduction. Therefore, we may need to distinguish between two states: the healthy state, in which retinol is not oxidized, and the disease state, in which retinol is oxidized, for example due to fasting or exercise. In the healthy state, citral does not appear to be beneficial, since it may be genotoxic. In the disease state, it seems to me that citral could still be beneficial, since it seems to be less genotoxic than RA, is not predicted to interact with RAR, RXR or ROR nuclear receptors, and (especially geranial) only interacts with a limited amount of proteins. Additionally, the lower lipophilicity of the glucuronides (0.11 for geranic acid glucuronide vs 2.5 for retinoyl glucuronide) should make enterohepatic circulation recirculation significantly less likely.
Finally, I recently had the idea that immunogenicity of retinol could be due to an allergic response as opposed to the fact that its metabolites are toxic. If that is the case, citral might not elicit an immune response simply due to the fact that we haven’t been exposed to it since birth as we have to retinol.
Bibliography
Agatonovic-Kustrin, S., E. Kustrin, V. Gegechkori and D. W. Morton (2020). "Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression." Adv Exp Med Biol 1260: 283-296.
Chung, Y. T., K. A. Matkowskyj, H. Li, H. Bai, W. Zhang, M.-S. Tsao, J. Liao and G.-Y. Yang (2012). "Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma." Modern Pathology 25(5): 758-766.
Hoang, S. A., A. Oseini, R. E. Feaver, B. K. Cole, A. Asgharpour, R. Vincent, M. Siddiqui, M. J. Lawson, N. C. Day, J. M. Taylor, B. R. Wamhoff, F. Mirshahi, M. J. Contos, M. Idowu and A. J. Sanyal (2019). "Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease." Scientific Reports 9(1): 12541.
Lu, Y., S. Bratton, J. M. Heydel and A. Radominska-Pandya (2008). "Effect of retinoids on UDP-glucuronosyltransferase 2B7 mRNA expression in Caco-2 cells." Drug Metab Pharmacokinet 23(5): 364-372.
Samokyszyn, V. M., W. E. Gall, G. Zawada, M. A. Freyaldenhoven, G. Chen, P. I. Mackenzie, T. R. Tephly and A. Radominska-Pandya (2000). "4-Hydroxyretinoic Acid, a Novel Substrate for Human Liver Microsomal UDP-glucuronosyltransferase(s) and Recombinant UGT2B7 *." Journal of Biological Chemistry 275(10): 6908-6914.
Wruck, W. and J. Adjaye (2017). Supplementary material for „Meta-analysis reveals up-regulation of cholesterol processes in non-alcoholic and down-regulation in alcoholic fatty liver disease“.
I briefly annotated this figure from (Carballo, Honorato et al. 2018), adding the effects of all-trans-retinoic acid and citral.
Bibliography
Carballo, G. B., J. R. Honorato, G. P. F. de Lopes and T. C. L. d. S. e. Spohr (2018). "A highlight on Sonic hedgehog pathway." Cell Communication and Signaling 16(1): 11.