Sebum: Physical Chemical Properties, Macromolecular Structure, and Effects of Ingredients

15 May

INTRODUCTION
Sebum  is a hallmark characteristic of oily skin, which  typifies  or is usually associ- ated  with  acne-prone skin.  The goal  of this  chapter is to present recent  findings regarding the macromolecular structure of sebum and  the  influence of variations in composition of sebum on that  macromolecular structure. It is further intended to discuss how  these  findings might  relate  to the  pathogenesis of acne.  In order to introduce a basis  for this  research, a brief  review  of the  current knowledge of the composition of sebum is in order,  although some  repetition of information in other   chapters  on  this   subject   is  likely.   After   this   review,   the  results  of  the thermal analysis of model  sebum using  differential scanning calorimetry (DSC) are presented along  with  an attempt to provide an explanation of the phase  beha- vior,  as it relates  to sebum composition and  to variations in the  composition that might  occur as part  of a disease state such as acne. Further studies of the influence of vehicles  on the phase  behavior are presented, along  with  a discussion of how an imbalance in typical  phase  behavior may  be relevant to the pathogenesis of acne.

Toward that  end,  our  findings show  that  a model  of sebum is a mixture of solid  and  liquid phases. We  speculate that  the  liquid phase   helps   dissolve or “soften” the solid  phase  and  that  these  two  phases exist in a delicate balance.  We further speculate that if this balance  is altered, the consequences could  be blockage of the sebaceous duct and of the infundibulum if the liquid part of sebum is too low and  can no longer  dissolve the solid part.  This could  result  from action of Propioni- bacterium acnes bacteria  on the sebum or from metabolic alterations in sebum com- position in situ.

ORIGIN OF SEBUM

Sebum  is the  oily  secretion of the  sebaceous gland  (Fig.  1). This  “oil  gland”  is located   juxtaposed to  the  hair  follicle.  The  large  ducts   of  the  hair  follicles  are filled with  this white  pasty  sebaceous material derived from the sebaceous gland. Sebaceous   glands are  generally found all  over  the  body,  except  on  the  palms, soles, and dorsum of the feet (1). Most of the glands are associated with hair follicles and  hence  are termed pilosebaceous glands. In humans, they  are concentrated on the  scalp,  forehead, and  face, where there  may  be as many  as 400 to 900 glands/ cm2  and  up to 1600 glands/cm2  on the nose (2). Sebaceous  follicles are particularly

abundant in the face, ear canal,  v-shaped parts  of the face, and  chest,  and  on the sides  of the upper arm. These skin areas  are hence relatively greasy.  The sebaceous gland,   though present during  childhood, is  very  small.  At  puberty, the  gland becomes enlarged (3). This  enlargement and  increased activity  of the  sebaceous gland at puberty is primarily under androgen control  (4).

SEBUM CHEMISTRY

The chemical  composition and  physical properties of sebum have  been studied by several  researchers and  are discussed next.

Composition of Sebum

Knowledge of sebum lipid components helps us to consider how a penetrating mol- ecule will react upon entering into the follicular  canal  and  how  this structure may theoretically be related to acnegenesis. The main  lipids  in human sebum are trigly- cerides,   wax  esters,   and   squalene with   smaller proportions of  cholesterol  and cholesterol esters  (4). Most  importantly, free  fatty  acids  (FFA) are  often  found in sebum and are formed from the triglycerides through the action of P. acnes. Bacterial lipases  convert triglycerides to mono- and diglycerides as well as FFA in the sebum, many  of which  are unique to the sebaceous glands (5).

The average composition of human skin surface  lipid  was given by Downing et al. (6) (Table 1) and of follicular  casts by Nordstrom et al. (7). Note the variability in the amounts of triglycerides and  FFA; this is attributed to the variable activity  of the bacterial lipase,  as discussed earlier.  The activity  of this enzyme seems  to be an individual variable unique to  each  person’s skin.  The  composition is compared with  that  of other  animals in a summary table  (Table 2). The wax  and  diol  esters

appear to  be  the  predominant class  of lipid  in  animals other  than  humans (8). Stewart et al. (9) have shown that wax esters  are lipids  that have their origin  exclu- sively in the sebum that is derived from sebaceous gland’s  synthetic machinery via de  nova  synthesis. In fact, the  same  authors have  proposed that  the  quantity  of endogenous lipids  synthesized de nova  per  cell relative to the sebocytes’  original endowment of exogenously derived lipids  is a major influence on the composition of secreted sebum.

The broad composition of the fatty  acid  components of various lipid  classes found in sebum are  given  in Table  3 (10). Thirty  percent to fourty  three  percent of the  fatty  acids  are unsaturated. Around 85% are  straight chains  as opposed to branched and  about  75% are  even  carbon  chain  lengths. The  monounsaturated fatty  acids  of human sebum are characterized by the unusual placing of a double bond  at position D6; this differs  from other  animals where the D9 monounsaturates are  predominant (4). In fact,  recent  studies (11) have  identified a D6-desaturase found in differentiating the  sebocytes from  the  suprabasal layer  of the  sebaceous gland;  this  enzyme forms  the double bonds at the D6 position. This suggests that the  gland  tightly  regulates the  formation of the  D6 fatty  acids  at the  appropriate time  during lipogenesis. These  acids  are  found in greatest abundance in sebum from   adults.  Human  sebum is  unique in  that   it  contains  dienoic   acids   with double bonds at positions D5 and  D8 and  at positions D7 and  D10. These constitute

2% to 3% of the total fatty acid content. The major form was identified as 18:2D5, 8 and, because of its presence in sebum, was named sebaleic acid (4). Branched chain acids  are present, which  are predominantly iso- and  anteiso-isomers, but there  are also smaller amounts of branched chain  acids,  in which  the methyl branch occurs at other  positions in the  chain.  Acids  having two  or three  methyl branches may also be present. Up to half of the fatty  acids  of sebum are monounsaturated with double  bonds  in  the   unusual  D6  position.  The  monounsaturated  fatty   acids include iso- and  anteiso-branched species,  but no internally branched or multibranched species. The fatty alcohols of the wax esters contain chain branching

and  unsaturation, similar to the fatty acids  (12). The fatty acid composition of wax esters  has been shown to vary  with  age in humans (4).

Several  other  authors have  also  examined the  fatty  acid  and  fatty  alcohol components of the  various lipid  classes  found in sebum. The  major  portion of the fatty  acids  in sebum are chain  lengths of C16 carbons. However, after this, it depends on  whether one  is  looking   at  saturated  or  unsaturated fatty  acids (7,9,12,13). For  example, for  saturated fatty  acids,  the  C14:0 exhibited the  next higher fraction  followed by C15:0, then  C18:0. For unsaturated fatty  acids,  C16 and  then  C18 carbon  chains  predominate. The  C16:1 chain  is characterized by the  large   amounts  of  C16:1D6  fatty   acids   shown  in  follicular  casts  (7).  The recent  discovery of the D6 fatty  acid  desaturase in differentiating sebocytes was mentioned earlier.  The straight chain  fatty  acids  that  are synthesized mainly by the  sebaceous glands are  C14:0, C14:1, C16:0, C16:1, and  C18:2 D5,8, because these  increased  with   increasing ratios   of  wax  esters   (of  sebaceous origin)   to cholesterolþcholesterol  esters   (both   of  exogenous  origin)   in  sebum  samples from  different age subjects.  Fatty  acids  that  circulate in the blood,  namely C18:0, C18:1, and  C18:2 D9,12, tended to decrease with  increasing ratios  of wax esters  to cholesterol þ cholesterol  esters,   suggesting  their   exogenous  origin   in  sebum. Stewart et al. (9) found that  the  fatty  acids  of triglycerides tended to follow  the same  compositions as the  FFA except  that  they  tended to have  a higher level of saturated fatty  acids.  Although Nordstrom  et  al.  (7)  found that   in  follicular casts, the triglycerides lacked the C16:1D6 and there were significantly higher rela- tive amounts of saturated fatty  acids  in these  triglycerides.

Regarding the  remaining lipid  classes,  Stewart et al. (9) reported that  wax esters  contained lower  amounts of  C18:0, C18:1, and  linoleate than  other  lipid classes,  suggesting that  very  few  exogenous lipids  get  into  the  wax  esters.  Wax esters  also  contain more  C14:1 and  C16:1 and  less  C14:0 and  C16:0 than  other lipid  classes.  These  findings suggest that  there  is some  mechanism for differential distribution of fatty acids among the various lipid classes. Regarding the polyunsa- turated fatty acids present in amounts less than 2% to 3%, linoleic acid (C18:2 D9,12) decreases and  sebaleic  acid  (C18:2 D5,8) increases as  the  ratio  of wax  esters  to cholesterol þ cholesterol esters  increases, leading again  to the conclusion that  lino- leic acid is an exogenous lipid.

A feature of human sebum is its high  squalene to the  cholesterol ratio.  The amount of cholesterol is very  small  compared to the amount of squalene. In fact, the  sebaceous gland has  an  incomplete enzyme system and  is unable to convert squalene to cholesterol (4). This suggests that  the source  of cholesterol in isolated sebum is of epidermal origin  rather than  sebaceous.

Copious amounts of phospholipids are required to support the cellular  and subcellular membranes of  the  expanding sebaceous cells  during their  differen- tiation.  In the  final  stages  of differentiation, when the  membranes are  degraded, the  phospholipids also  disappear, and  it is assumed that  the  fatty  acids  become esterified with  whatever hydroxyl lipids   that  are  available. These  mechanisms explain why sebum does not contain phospholipids, despite the holocrine character of the sebaceous gland  function (14).

Physical Properties of Sebum

The physical properties of sebum have been investigated a number of times. Braun- Falco et al. (15) claimed that a lipid obtained from the scalp using  ether extraction is a liquid at body  temperature. The fact that  this  lipid  is obtained from  the  scalp, where usually no  comedones are  found, was  ignored. Other   workers (16 – 18) have also investigated the physical properties of sebum and  its role in acnegenesis, without the concern that the sebum obtained was from the areas  of the skin where acne  does  not  normally occur.  Hence,  if any  relationship does  exist  between the physical properties  of  sebum  and   acne,   it  would  be  erroneous  to  use   these studies. Still other  papers (19) used  ether  to extract  it from  the foreheads and  this was  then  analyzed. Here  again,  only  the  surface  lipid  was  analyzed and  not  the lipid  from  the  inner  acrofundibulum. Here,  a major  assumption was  made that sebum is a liquid and  hence  flows  out,  and  this  was  analyzed. It is reasonable to postulate that  since  sebum is  a  mixture of different substances, it  will  exist  in more  than  one phase. Some phases may  be liquids whereas others  may  be solids at body  temperature.

Some of the physical properties have been enumerated. The physical proper- ties of sebum are summarized in Table 4.

Freezing Temperature

Although Miescher  and Schoenberg (20) isolated forehead sebum in normal volun- teers  and  have  assigned the freezing point  of 338C to 358C to sebum, Butcher  and Coonin   (19)  also  isolated  forehead  sebum  from   normal  volunteers  and   have ascribed a value  of 158C to 178C. From  these  studies, it was  not  clear if sebum is a  liquid or  a  solid  at  body  temperature. Since  sebum is  a  mixture of different

lipidic  substances, it is assumed that  it will  not  have  a single  freezing point,  but rather a range  of temperatures in which  transitions from  a liquid to a solid  takes place.  Butcher  and  Coonin  (19) claim  that  the  sebum sample started to freeze  up to 308C, but the whole  sample solidified at 158C to 178C and  stopped flowing.

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