established to be 30‑60%. for these reasons, physician- and patient-education programs were initiated, recommending that for women of child-bearing age, contraception be initiated a month before starting oral (or topical) isotretinoin, and continue for a month after treatment ended. in addition to the approved use for treating acne vulgaris, researchers have investigated off-label applications for dermatological conditions, such as rosacea, psoriasis, and other conditions. rosacea was reported as responding favorably to doses lower than used for acne. isotretinoin in combination with ultraviolet light was shown affective for treating psoriasis. isotretinoin in combination with injected interferon-alpha showed some potential for treating genital warts. isotretinoin in combination with topical fluorouracil or injected interferon-alpha showed some potential for treating precancerous skin lesions and skin cancer. topical retinoic acid and retinol retinoids: tretinoin is all-trans-retinoic acid; initial tradename: retin-a. isotretinoin is 13-cis-retinoic acid; initial tradename: accutane. etretinate and acitretin, its non-esterified metabolite, are used orally to treat severe psoriasis. retinoic acids tretinoin (all-trans-retinoic acid) and isotretinoin (13-cis-retinoic acid) are prescription topical medications used to treat moderate to severe cystic acne and acne not responsive to other treatments. these are usually applied as a skin cream to the face after cleansing to remove make-up and skin oils. tretinoin and isotretinoin act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (rar) and the retinoid x receptors (rxr). these events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation. the retinoid-receptor complex competes for coactivator proteins of ap-1, a key transcription factor involved in inflammation. retinoic acid products also reduce sebum secretion, a nutrient source for bacteria, from facial pores. these drugs are us-designated pregnancy category c (animal reproduction studies have shown an adverse effect on the fetus), and should not be used by pregnant women or women who are anticipating becoming pregnant. many countries established a physician- and patient- education pregnancy prevention policy. trifarotene is a prescription retinoid for the topical treatment acne vulgaris. it functions as a retinoic acid receptor (rar)-γ agonist. non-prescription topical products that have health claims for reducing facial acne, combating skin dark spots and reducing wrinkles and lines associated with aging often contain retinyl palmitate. the hypothesis is that this is absorbed and desterified to free retinol, then converted to retinaldehyde and further metabolized to all-trans-retinoic acid, whence it will have the same effects as prescription products with fewer side effects. there is some ex vivo evidence with human skin that esterified retinol is absorbed and then converted to retinol. in addition to esterified retinol, some of these products contain hydroxypinacolone retinoate, identified as esterified 9-cis-retinoic acid. synthesis biosynthesis carotenoid synthesis takes place in plants, certain fungi, and bacteria. structurally carotenes are tetraterpenes, meaning that they are synthesized biochemically from four 10-carbon terpene units, which in turn were formed from eight 5-carbon isoprene units. intermediate steps are the creation of a 40-carbon phytoene molecule, conversion to lycopene via desaturation, and then creation of ionone rings at both ends of the molecule. β-carotene has a β-ionone ring at both ends, meaning that the molecule can be divided symmetrically to yield two retinol molecules. α-carotene has a β-ionone ring at one end and an ɛ-ionone ring at the other, so it has half the retinol conversion capacity. vitamin a biosynthesis from β-carotene in most animal species, retinol is synthesized from the breakdown of the plant-formed provitamin, β-carotene. first, the enzyme beta-carotene 15,15'-dioxygenase (bco-1) cleaves β-carotene at the central double bond, creating an epoxide. this epoxide is then attacked by water creating two hydroxyl groups in the center of the structure. the cleavage occurs when these alcohols are oxidized to the aldehydes using nad+. the resultant retinal is then quickly reduced to retinol by the enzyme retinol dehydrogenase. omnivore species such as dogs, wolves, coyotes and foxes in general are low producers of bco-1. the enzyme is lacking in felids (cats), meaning that vitamin a requirements are met from the retinyl ester content of prey animals. industrial synthesis β-ionone ring β-carotene can be extracted from fungus blakeslea trispora, marine algae dunaliella salina or genetically modified yeast saccharomyces cerevisiae, starting with xylose as a substrate. chemical synthesis uses either a method developed by basf or a grignard reaction utilized by hoffman-la roche. the world market for synthetic retinol is primarily for animal feed, leaving approximately 13% for a combination of food, prescription medication and dietary supplement use. industrial methods for the production of retinol rely on chemical synthesis. the first industrialized synthesis of retinol was achieved by the company hoffmann-la roche in 1947. in the following decades, eight other companies developed their own processes. β-ionone, synthesized from acetone, is the essential starting point for all industrial syntheses. each process involves elongating the unsaturated carbon chain. pure retinol is extremely sensitive to oxidization and is prepared and transported at low temperatures and oxygen-free atmospheres. when prepared as a dietary supplement or food additive, retinol is stabilized as the ester derivatives retinyl acetate or retinyl palmitate. prior to 1999, three companies, roche, basf and rhone-poulenc controlled 96% of global vitamin a sales. in 2001, the european commission imposed total fines of 855.22 million euros on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989. roche sold its vitamin division to dsm in 2003. dsm and basf have the major share of industrial production. a biosynthesis alternative utilizes genetically engineered yeast species saccharomyces cerevisiae to synthesize retinal and retinol, using xylose as a starting substrate. this was accompished by having the yeast first synthesize β-carotene and then the cleaving enzyme β-carotene 15,15'-dioxygenase to yield retinal. research brain animal research (on mice), which is pre-clinical, also found retinoid acid, the bioactive metabolite of vitamin a, to have an effect on brain areas responsible for memory and learning. cancer meta-analyses of intervention and observational trials for various types of cancer report mixed results. supplementation with β-carotene did not appear to decrease the risk of cancer overall, nor specific cancers including: pancreatic, colorectal, prostate, breast, melanoma, or skin cancer generally. high-dose β-carotene supplementation unexpectedly resulted in a higher incidence of lung cancer and of total mortality in people who were cigarette smokers. for dietary retinol, no effects were observed for high dietary intake and breast cancer survival, risk of liver cancer, risk of bladder cancer or risk of colorectal cancer, although the last review did report lower risk for higher beta-carotene consumption. in contrast, an inverse association was reported between retinol intake and relative risk of esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, lung cancer, melanoma, and cervical cancer. for lung cancer, an inverse association was also seen for beta-carotene intake, separate from the retinol results. when high dietary intake was compared to low dietary intake, the decreases in relative risk were in the range of 15 to 20%. for gastric cancer, a meta-analysis of prevention trials reported a 29% decrease in relative risk from retinol supplementation at 1500 μg/day. fetal alcohol spectrum disorder fetal alcohol spectrum disorder (fasd), formerly referred to as fetal alcohol syndrome, presents as craniofacial malformations, neurobehavioral disorders and mental disabilities, all attributed to exposing human embryos to alcohol during fetal development. the risk of fasd depends on the amount consumed, the frequency of consumption, and the points in pregnancy at which the alcohol is consumed. ethanol is a known teratogen, i.e., causes birth defects. ethanol is metabolized by alcohol dehydrogenase enzymes into acetaldehyde. the subsequent oxidation of acetaldehyde into acetate is performed by aldehyde dehydrogenase enzymes. given that retinoic acid (ra) regulates numerous embryonic and differentiation processes, one of the proposed mechanisms for the teratogenic effects of ethanol is a competition for the enzymes required for the biosynthesis of ra from vitamin a. animal research demonstrates that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for aldehyde dehydrogenase activity. in this model, acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase. ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. thus, animal research supports the reduction of retinoic acid activity as an etiological trigger in the induction of fasd. malaria malaria and vitamin a deficiency are both common among young children in sub-saharan africa. vitamin a supplementation to children in regions where vitamin a deficiency is common has repeatedly been shown to reduce overall mortality rates, especially from measles and diarrhea. for malaria, clinical trial results are mixed, either showing that vitamin a treatment did not reduce the incidence of probable malarial fever, or else did not affect incidence, but did reduce slide-confirmed parasite density and reduced the number of fever episodes. the question was raised as to whether malaria causes vitamin a deficiency, or vitamin a deficiency contributes to the severity of malaria, or both. researchers proposed several mechanisms by which malaria (and other infections) could contribute to vitamin a deficiency, including a fever-induced reduction in synthesis of retinal-binding protein (rbp) responsible for transporting retinol from liver to plasma and tissues, but reported finding no evidence for a transient depression or restoration of plasma rbp or retinol after a malarial infection was eliminated. in history frederick gowland hopkins, 1929 nobel prize for physiology or medicine in 1912, frederick gowland hopkins demonstrated that unknown accessory factors found in milk, other than carbohydrates, proteins, and fats were necessary for growth in rats. hopkins received a nobel prize for this discovery in 1929. by 1913, one of these substances was independently discovered by elmer mccollum and marguerite davis at the university of wisconsin–madison, and lafayette mendel and thomas burr osborne at yale university. mccollum and davis ultimately received credit because they submitted their paper three weeks before mendel and osborne. both papers appeared in the same issue of the journal of biological chemistry in 1913. the "accessory factors" were termed "fat soluble" in 1918, and later "vitamin a" in 1920. in 1919, harry steenbock (university of wisconsin–madison) proposed a relationship between yellow plant pigments (beta-carotene) and vitamin a. in 1931, swiss chemist paul karrer described the chemical structure of vitamin a. retinoic acid and retinol were first synthesized in 1946 and 1947 by two dutch chemists, david adriaan van dorp and jozef ferdinand arens. george wald, 1967 nobel prize for physiology or medicine during world war ii, german bombers would attack at night to evade british defenses. in order to keep the 1939 invention of a new on-board airborne intercept radar system secret from germany, the british ministry of information told newspapers an unproven claim that the nighttime defensive success of royal air force pilots was due to a high dietary intake of carrots rich in beta-carotene, successfully convincing many people. in 1967, george wald shared the nobel prize in physiology and medicine for his work on chemical visual processes in the eye. wald had demonstrated in 1935 that photoreceptor cells in the eye contain rhodopsin, a chromophore composed of the protein opsin and 11-cis-retinal. when struck by light, 11-cis-retinal undergoes photoisomerization to all-trans-retinal and via signal transduction cascade send a nerve signal to the brain. the all-trans-retinal is reduced to all-trans-retinol and travels back to the retinal pigment epithelium to be recycled to 11-cis-retinal and reconjugated to opsin. wald's work was the culmination of nearly 60 years of research. in 1877, franz christian boll identified a light-sensitive pigment in the outer segments of rod cells of the retina that faded/bleached when exposed to light, but was restored after light exposure ceased. he suggested that this substance, by a photochemical process, conveyed the impression of light to the brain. the research was taken up by wilhelm kühne, who named the pigment rhodopsin, also known as "visual purple." kühne confirmed that rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions, and that it was this chemical decomposition that stimulated nerve impulses to the brain. research stalled until after identification of "fat-soluble vitamin a" as a dietary substance found in milkfat but not lard, would reverse night blindness and xerophthalmia. in 1925, fridericia and holm demonstrated that vitamin a deficient rats were unable to regenerate rhodopsin after being moved from a light to a dark room.